Gene Summary

Gene:CDKN2A; cyclin dependent kinase inhibitor 2A
Aliases: ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A
Summary:This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 2A
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (17)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
MelanomaCDKN2A and Melanoma View Publications815
Head and Neck CancersCDKN2A Mutations in Head and Neck CancerPrognostic
CDKN2A is one of the most frequently altered genes in head and neck cancers. Hypermethylation and LOH lead to inactivation of the gene.
View Publications585
Lung CancerCDKN2A and Lung Cancer View Publications522
Colorectal CancerCDKN2A and Colorectal Cancer View Publications430
Pancreatic CancerCDKN2A Mutation in Pancreatic Cancer View Publications448
Melanoma, FamilialCDKN2A and Familial Melanoma View Publications319
Breast CancerCDKN2A and Breast Cancer View Publications315
Bladder CancerCDKN2A deletion in Bladder Cancer View Publications174
MesotheliomaCDKN2A Deletion in Mesothelioma View Publications154
OsteosarcomaCDKN2A and Osteosarcoma View Publications111
Pancreatic Cancer, FamilialCDKN2A Mutation in Familial Pancreatic Cancer View Publications85
Ewing's SarcomaCDKN2A Deletion in Ewing's SarcomaPrognostic
CDKN2A alterations occurred between 13% and 31% of Ewing's Sarcoma and were a significant prognostic factor in a meta analysis of 6 studies with combined 188 patients (Honoki et al, 2007).
View Publications30
NeurofibromatosisCDKN2A and Malignant Transformation in Neurofibromatosis 1 View Publications29
RhabdomyosarcomaCDKN2A and Rhabdomyosarcoma View Publications17
Hodgkin LymphomaCDKN2A Expression in Hodgkin's Disease View Publications15
Wilms TumourCDKN2A Expression in Wilms' Tumour View Publications6
Adrenocortical CancerCDKN2A and Adrenocortical Carcinoma View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CDKN2A (cancer-related)

Sun S, Hu Z, Huang S, et al.
REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression.
J Cancer Res Clin Oncol. 2019; 145(9):2273-2283 [PubMed] Related Publications
OBJECTIVES: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation plus TTF-1 low expression (KC subgroup). The aim of this study was to identify valuable biomarkers by searching the candidate molecules that contribute to lung adenocarcinoma pathogenesis, especially KC subtype.
MATERIALS AND METHODS: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after silencing the REG4 expression.
RESULTS: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutant lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduces cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce cell cycle arrest by regulating G2/M checkpoint and E2F targets.
CONCLUSION: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanisms of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.

Yoo SK, Song YS, Lee EK, et al.
Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.
Nat Commun. 2019; 10(1):2764 [PubMed] Free Access to Full Article Related Publications
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF

Gao S, Wang J, Tian S, Luo J
miR‑9 depletion suppresses the proliferation of osteosarcoma cells by targeting p16.
Int J Oncol. 2019; 54(6):1921-1932 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) is a common primary malignancy in adolescents and children. MicroRNAs (miRNAs or miRs) can regulate the progression of OS. Herein, we explored the target genes and effects of miR‑9 in OS. Cell growth, colony formation and cell cycle were respectively examined using a cell counting kit‑8 (CCK‑8), crystal violet staining and flow cytometry. The target gene of miR‑9 was predicted according to the website. Luciferase activity was examined using a dual luciferase reporter gene assay kit. The corresponding factors levels were analyzed by carrying out reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. A mouse model of OS was also established and the volume and weight of the tumors of the mice with OS were measured. The levels of p16 in the mice with OS were detected by immunohistochemistry (IHC). The data revealed a high expression of miR‑9 and a low expression of p16 in the OS tissue. p16 was found to be the target gene for miR‑9 in OS. miR‑9 depletion decreased the proliferation and colony formation of Saos‑2 cells by arresting the cells at the G1 phase, accompanied by the downregulation of cyclin A, cyclin D1 and c‑Myc expression levels. Moreover, miR‑9 depletion inhibited the phosphorylation of p38, c‑Jun N‑terminal kinase (JNK) and extracellular signal‑regulated kinase (ERK). In vivo, miR‑9 depletion decreased the tumor volume and weight and increased p16 expression in the mouse tumor tissues. Nevertheless, p16 silencing reversed the suppressive effects of miR‑9 inhibitors on OS cells. On the whole, the findings of this study substantiate that miR‑9 depletion suppresses cell proliferation by targeting p16 in OS and by mediating the activation of the ERK/p38/JNK pathway.

Kwon WA, Yoon MY, Kim SH, et al.
Single-Center Analysis of Human Papillomavirus Infection and P16INK4A Expression among Korean Patients with Penile Cancer.
Biomed Res Int. 2019; 2019:6940582 [PubMed] Free Access to Full Article Related Publications
Purpose: This study aimed to evaluate the statuses of P16INK4A expression and human papillomavirus (HPV) infection among patients with penile cancer at a single Korean institution.
Patients and Methods: Fourteen patients with penile cancer at our center were retrospectively identified and their clinicopathological data were analyzed. The patients' HPV and P16INK4A expression status (a known tumor suppressor protein) were tested using genotyping with a DNA chip assay and immunohistochemical staining, respectively. The results regarding HPV status were compared to those from another Asian study.
Results: The mean age at diagnosis was 60 years (range: 34-86 years). The median tumor size was 3.0 cm (range: 0.6-4.7 cm). Ten tumors were located on the penile glans. Five patients tested positive for HPV DNA (5/14, 36%) and all cases involved HPV type 16 (5/5, 100%). Positive expression of P16INK4A was observed in 6 cases (6/14, 43%). Among the HPV positive cases, 80% of cases (4/5) were also positive for P16INK4A. The prevalence of HPV infection in our study (36%) was higher than in a previous Asian study (23%).
Conclusions: This is the first study to evaluate the prevalence of HPV infection and P16INK4A expression among patients with penile cancer at a single Korean institution. The prevalence of HPV (36%) was slightly higher than the results from a previous Asian study. Additional multi-center studies are needed to better understand penile cancer in Korea and to identify biomarkers that can determine high-risk cases and predict their prognosis.

Wujcicka W, Zając A, Stachowiak G
Impact of
In Vivo. 2019 May-Jun; 33(3):917-924 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The aim of this study was to determine the joint effect of single nucleotide polymorphisms (SNPs) of MDM2, TP53, and CDKN2A (P14ARF) genes on the onset and course of endometrial cancer (EC) in postmenopausal women.
MATERIALS AND METHODS: The study group consisted of 144 EC women and 50 non-cancer controls. MDM2 rs22279744, TP53 rs1042522, and P14ARF rs3088440, rs3731217, and rs3731245 SNPs were analysed.
RESULTS: The double-SNP combinations T-C, T-T, or T-G in MDM2 SNP 309 and P14ARF polymorphisms decreased EC risk. The triple-SNP combinations T-C-T, T-C-G, or T-T-G in MDM2 SNP and two P14ARF polymorphisms decreased EC risk. The multiple-SNP combination T-C-T-G in MDM2 and three P14ARF polymorphisms decreased EC risk. The G-Arg-C-T-G carriers were at increased EC risk, while the T-Arg-C-T-G carriers were at decreased EC risk.
CONCLUSION: MDM2 SNP309 plays a role in EC onset in postmenopausal women.

Abolhassani M, Asadikaram G, Paydar P, et al.
Organochlorine and organophosphorous pesticides may induce colorectal cancer; A case-control study.
Ecotoxicol Environ Saf. 2019; 178:168-177 [PubMed] Related Publications
OBJECTIVES: Among the numerous agents, genetic factors and environmental elements such as pesticides have an important role in colorectal cancer (CRC) incidence. The present study aimed to investigate the probable-role of some organochlorine pesticides (OCPs) and organophosphorous pesticides (OPPs) in patients with CRC.
METHODS: In this case-control study, 42 patients with CRC and 30 healthy subjects were selected. The serum levels of some OCPs (α-HCH, β-HCH, γ-HCH, 2,4 DDE, 4,4 DDE, 2,4DDT and 4,4DDT) were measured by gas chromatography (GC) method. Serum levels of malondialdehyde (MDA), and total antioxidant capacity (TAC) as well as the enzyme activity of acetylcholinesterase (AChE) and arylesterase activity of Paraoxonase-1 (PON-1) were evaluated in all participants. The methylation specific PCR (MSP) assay was used for determining the methylation status of CpG island of p16 and MGMT genes in CRC patients.
RESULTS: The mean serum levels of each OCPs were significantly higher in the patient group compared to the control group (P < 0.001). The AChE and arylesterase activity of PON-1 in the patient group were significantly lower than the control group (P < 0.001). The mean serum levels of MDA and TAC in the serum of the patient group were significantly higher than the control group (P < 0.001 and P < 0.002, respectively). The current findings demonstrated significantly hypermethylation of p16 promoter in CRC patients.
CONCLUSION: Regarding the higher levels of OCPs in CRC patients, along with hypermethylation of the p16 promoter gene, diminishing in AChE and PON-1 activity and increasing in oxidative stress factors, the role of OCPs and OPPs in the CRC progression in the South-East of Iran may be assumed.

Oue N, Sentani K, Sakamoto N, et al.
Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells.
Int J Clin Oncol. 2019; 24(7):771-778 [PubMed] Related Publications
Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

Huang B, Ji L, Liang B, et al.
A simple and low-cost screen printed electrode for hepatocellular carcinoma methylation detection.
Analyst. 2019; 144(10):3282-3288 [PubMed] Related Publications
There is a great demand for robust diagnostic and prognostic approaches for Hepatocellular Carcinoma (HCC). DNA methylation, a common epigenetic modification, has been found in many promoter regions of tumor suppressor genes. Hypermethylation of these gene promoters will repress the gene transcription and lead to the occurrence of cancers. The abnormal methyation level of the p16 gene promoter could be a promising marker for the detection of HCC. The adsorption affinities between different DNA bases and AuNPs are not the same. After bisulfite treatment and asymmetric PCR, methylation and unmethylation sequences can be changed into guanine-enriched and adenine-enriched sequences, respectively. A home-made gold nanoparticle modified screen printed carbon electrode (AuNP-SPCE) was employed to distinguish the adsorption affinities between guanine-enriched and adenine-enriched sequences, which could be used to analyze the level of DNA methylation. Several key experimental factors were investigated and optimized. The results had shown that the optimal AuNP electrodeposition time was 100 s and 15 min of adsorption could distinguish guanine-enriched and adenine-enriched sequences with a concentration of 100 nM at 25 °C. The detection limit of our AuNP-SPCE was 1.1 ng, and the assay had a good sensitivity of 10% methylation change and was able to distinguish only one methylated CpG site. What's more, the RSD over three assays with a disposable AuNP-SPCE was ≤7.2%. The assay was applied to real samples including cell lines and clinical tissues. Compared with normal hepatic cell lines and normal tissues, lower signals of HCC cell lines and cancer tissues were observed, respectively. It had shown a good discrimination of the abnormal methylation level of the p16 gene promoter.

Xiao Z, He Y, Liu C, et al.
Targeting P16INK4A in uterine serous carcinoma through inhibition of histone demethylation.
Oncol Rep. 2019; 41(5):2667-2678 [PubMed] Free Access to Full Article Related Publications
Uterine serous carcinoma (USC) is a subtype of endometrial cancer. Compared with endometrial endometroid carcinoma, the majority of USC cases are more aggressive. Cyclin-dependent kinase inhibitor 2A (P16INK4A) is a canonical tumor suppressor that blocks cell cycle progression; however, P16INK4A is overexpressed in USC. The aim of the present study was to determine the role of P16INK4A in P16INK4A‑positive endometrial cancer, with the hope of elucidating a novel therapeutic approach for this type of malignancy. A total of 2 endometrial cancer cell lines, ETN‑1 and EFE‑184, were selected for further investigation, due to them being known to express high levels of P16INK4A. Using short hairpin RNA targeting P16INK4A, P16INK4A was downregulated in these cancer cell lines. Cell viability and migration were examined via 2D/3D clonogenic and wound healing assays. Subsequently, GSK‑J4, a histone demethylase inhibitor, was employed to deplete P16INK4A in these cancer cell lines and an ex vivo culture system of a patient‑derived xenograft (PDX) endometrial tumor sample. Following P16INK4A knockdown, the proliferation and migration of ETN‑1 and EFE‑184 cells markedly declined. When exposed to GSK‑J4, the levels of KDM6B and P16INK4A were almost completely abrogated, and the cell viability was significantly reduced in these cell lines and the ex vivo‑cultured PDX tumor explants. The association between the levels of P16INK4A, lysine demethylase 6B (KDM6B) and the methylation status of histone 3 lysine 27 (H3K27) in these cell lines and the human USC tumor sample was also demonstrated. P16INK4A appears to be oncogenic in a number of endometrial cancer cell lines. The level of P16INK4A is associated with the methylation status of H3K27. Increased methylation of H3K27 coexists with downregulation of KDM6B and, subsequently, P16INK4A, which reduces cell proliferation and invasiveness in endometrial cancer. The observations of the present study may enable the development of a novel therapeutic strategy for P16INK4A‑positive endometrial cancer, particularly USC.

Fontana R, Ranieri M, La Mantia G, Vivo M
Dual Role of the Alternative Reading Frame ARF Protein in Cancer.
Biomolecules. 2019; 9(3) [PubMed] Free Access to Full Article Related Publications
The CDKN2a/ARF locus expresses two partially overlapping transcripts that encode two distinct proteins, namely p14ARF (p19Arf in mouse) and p16INK4a, which present no sequence identity. Initial data obtained in mice showed that both proteins are potent tumor suppressors. In line with a tumor-suppressive role, ARF-deficient mice develop lymphomas, sarcomas, and adenocarcinomas, with a median survival rate of one year of age. In humans, the importance of ARF inactivation in cancer is less clear whereas a more obvious role has been documented for p16INK4a. Indeed, many alterations in human tumors result in the elimination of the entire locus, while the majority of point mutations affect p16INK4a. Nevertheless, specific mutations of p14ARF have been described in different types of human cancers such as colorectal and gastric carcinomas, melanoma and glioblastoma. The activity of the tumor suppressor ARF has been shown to rely on both p53-dependent and independent functions. However, novel data collected in the last years has challenged the traditional and established role of this protein as a tumor suppressor. In particular, tumors retaining ARF expression evolve to metastatic and invasive phenotypes and in humans are associated with a poor prognosis. In this review, the recent evidence and the molecular mechanisms of a novel role played by ARF will be presented and discussed, both in pathological and physiological contexts.

Singhi AD, George B, Greenbowe JR, et al.
Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers.
Gastroenterology. 2019; 156(8):2242-2253.e4 [PubMed] Related Publications
BACKGROUND & AIMS: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.
METHODS: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.
RESULTS: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.
CONCLUSIONS: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.

Mizuno Y, Chinen Y, Tsukamoto T, et al.
A novel method of amplified fluorescent in situ hybridization for detection of chromosomal microdeletions in B cell lymphoma.
Int J Hematol. 2019; 109(5):593-602 [PubMed] Related Publications
Chromosomal microdeletions frequently cause loss of prognostically relevant tumor suppressor genes in hematologic malignancies; however, detection of minute deletions by conventional methods for chromosomal analysis, such as G-banding and fluorescence in situ hybridization (FISH), is difficult due to their low resolution. Here, we describe a new diagnostic modality that enables detection of chromosomal microdeletions, using CDKN2A gene deletion in B cell lymphomas (BCLs) as an example. In this method, which we refer to as amplified-FISH (AM-FISH), a 31-kb fluorescein isothiocyanate (FITC)-conjugated DNA probe encoding only CDKN2A was first hybridized with the chromosome, and then labeled with Alexa Fluor 488-conjugated anti-FITC secondary antibody to increase sensitivity. CDKN2A signals were equally identifiable by AM-FISH and conventional FISH in normal mononuclear blood cells. In contrast, when two BCL cell lines lacking CDKN2A were analyzed, CDKN2A signals were not detected by AM-FISH, whereas conventional FISH yielded false signals. Furthermore, AM-FISH detected CDKN2A deletions in two BCL patients with 9p21 microdeletions, which were not detected by conventional FISH. These results suggest that AM-FISH is a highly sensitive, specific, and simple method for diagnosis of chromosomal microdeletions.

Sridharan DM, Enerio S, Wang C, et al.
Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure.
Life Sci Space Res (Amst). 2019; 20:101-112 [PubMed] Related Publications
There exists a wide degree of genetic variation within the normal human population which includes disease free individuals with heterozygote defects in major DNA repair genes. A lack of understanding of how this genetic variation impacts cellular phenotypes that inform cancer risk post heavy ion exposure poses a major limitation in developing personalized cancer risk assessment astronauts. We initiated a pilot study with Human Mammary Epithelial Cell strains (HMEC) derived from wild type, a p16 silenced derivative of wild type, and various genetic variants that were heterozygote for DNA repair genes; BRCA1, BRCA2 and ATM. Cells strains were exposed to different high and low LET radiation qualities to generate both simple and complex lesions and centrosome aberrations were examined as a surrogate marker of genomic instability and cancer susceptibility post different exposures. Our results indicate that centrosome aberration frequency is higher in the genetic variants under study. The aberration frequency increases with dose, complexity of the lesion generated by different radiation qualities and age of the individual. This increase in genomic instability correlates with elevated check-point activation post radiation exposure. These studies suggest that the influence of individual genetics on cell cycle regulation could modify the degree of early genomic instability in response to complex lesions and potentially define cancer predisposition in response to HZE exposure. These results will have significant implications in estimating cancer susceptibility in genetically variant individuals exposed to HZE particles.

Zhang H, Mao JS, Hu WF
Functional Genetic Single-Nucleotide Polymorphisms (SNPs) in Cyclin-Dependent Kinase Inhibitor 2A/B (CDKN2A/B) Locus Are Associated with Risk and Prognosis of Osteosarcoma in Chinese Populations.
Med Sci Monit. 2019; 25:1307-1313 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) encodes several tumor suppressor proteins. Aberrant genetic alterations in CDKN2A/B were found in some malignancies, which were believed to be associated with tumor originating and progression. We hypothesized that CDKN2A/B genetic polymorphisms might be associated with the risk of poorer prognosis of osteosarcoma in Chinese populations. MATERIAL AND METHODS We included 184 validated osteosarcoma cases and 185 cancer-free healthy controls in the study. Five single-nucleotide polymorphisms of CDKN2A/B (rs1063192, rs3218009, rs3217986, rs3217992, and rs3731257) were genotyped and underwent bioinformatic analysis. DNA from osteosarcoma individuals was isolated from frozen peripheral blood and DNA from healthy controls was extracted from fresh prepared peripheral blood. RESULTS An allele of the SNP rs3217992 is predictive for susceptibility to osteosarcoma, and it is associated with poorer prognosis of osteosarcoma. The GA and AA genotypes of rs3217992 are related to elevated risk of osteosarcoma. In addition, the GA and AA genotypes of rs3217992 in CDKN2A might indicate higher stage and increased risk of lung metastasis of osteosarcoma, resulting in worse prognosis. CONCLUSIONS Functional genetic polymorphisms in CDKN2A/B predict the susceptibility and outcome of osteosarcoma in Chinese individuals.

Bai Y, Shen Y, Yuan Q, et al.
Evaluation of Relationship between Occurrence of Liver Cancer and Methylation of Fragile Histidine Triad (FHIT) and P16 Genes.
Med Sci Monit. 2019; 25:1301-1306 [PubMed] Free Access to Full Article Related Publications
BACKGROUND We examined the level of fragile histidine triad (FHIT) and p16 gene methylation in patients with hepatocellular carcinoma and explored the relationship to liver cancer. MATERIAL AND METHODS There were 56 patients with primary liver cancer who were admitted to the hospital from July 2015 to October 2017 included in the liver cancer group, and 24 non-hepatoma patients (hepatitis A/hepatitis B/hepatitis C, liver cirrhosis, liver fibrosis, and fatty liver, alcoholic liver identified as a control group. Fasting venous blood samples were collected from the 2 groups. Methylation-specific PCR (MSP) was used to detect the methylation of FHIT and p16 genes in the 2 groups. The risk factors for lung cancer were analyzed by logistic regression. In addition, the effects of FHIT and p16 gene methylation on the diagnostic accuracy of liver cancer were calculated. RESULTS The incidence of FHIT and p16 methylation in serum from the liver cancer group was 51.8% and 67.9%, respectively. The incidence of FHIT and p16 methylation in the non-hepatoma group was 16.7% and 25.0%. There was a statistical statistically correlated with gender, and the methylation of FHIT and p16 genes (P<0.05). From logistic regression analysis results, methylation of p16 and FHIT genes was an independent risk factor for hepatocellular carcinoma with odds ratio (OR) values of 10.550 (2.313~48.116) and 8.239 (2.386~28.455), respectively. CONCLUSIONS The methylation of p16 and FHIT genes was an independent risk factor for hepatocellular carcinoma.

Cappellesso R, Lo Mele M, Munari G, et al.
Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers.
Pathol Res Pract. 2019; 215(5):957-962 [PubMed] Related Publications
Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.

Romo CG, Palsgrove DN, Sivakumar A, et al.
Widely metastatic IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics.
Diagn Pathol. 2019; 14(1):16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy.
CASE PRESENTATION: We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient's known brain primary and chemotherapy with temozolomide was initiated. The patient's rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation.
CONCLUSION: This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.

Oyama R, Kito F, Takahashi M, et al.
Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1.
Hum Cell. 2019; 32(2):202-213 [PubMed] Related Publications
Dedifferentiated chondrosarcoma is an aggressive mesenchymal tumor of the bone, and novel therapies are needed to improve its clinical outcomes. Patient-derived cell lines are essential tools for elucidating disease mechanisms associated with poor prognosis and for developing therapies. However, few lines and xenografts have been previously reported in dedifferentiated chondrosarcoma. We established a novel patient-derived dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1. Primary dedifferentiated chondrosarcoma tissues were obtained at the time of surgery and subjected to primary tissue culture. The cell line was established and authenticated by assessing DNA microsatellite short tandem repeats. The cells maintained in monolayer cultures exhibited constant growth, spheroid formation capacity, and invasion ability. When the cells were implanted into mice, they exhibited histological features similar to those of the original tumor. Genomic analysis of single nucleotide polymorphisms showed aberrant genomic contents. The DNA sequencing revealed the absence of IDH1/2 mutations. The global targeted sequencing revealed that the cell line preserved homozygous deletion of CDKN2A and CREBBP. A proteomic study by mass spectrometry unveiled similar but distinct molecular backgrounds in the original tumor and the established cell line, suggesting that tumor cell functions might be altered during the establishment of the cell line. Using a screening approach, four anti-cancer drugs with anti-proliferative effects at a low concentration were identified. In conclusion, a novel dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1, was successfully established from primary tumor tissues. The NCC-dCS1-C1 cell line will be a useful tool for investigations of the mechanisms underlying dedifferentiated chondrosarcomas.

Suszynska M, Klonowska K, Jasinska AJ, Kozlowski P
Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes.
Gynecol Oncol. 2019; 153(2):452-462 [PubMed] Related Publications
OBJECTIVE: Germline mutations occurring in the highly penetrant genes BRCA1 and BRCA2 are responsible for only certain cases of familial breast cancer (BC) and ovarian cancer (OC). Thus, the use of NGS multi-gene panel (MGP) testing has recently become very popular.
METHODS: To estimate a reliable BC and OC risk associated with pathogenic variants in the selected candidate BC/OC predisposition genes, a comprehensive meta-analysis of 48 MGP-based studies analyzing BC/OC patients was conducted. The role of 37 genes was evaluated, comparing, in total, the mutation frequency in ~120,000 BC/OC cases and ~120,000 controls, which guaranteed strong statistical support with high confidence for most analyzed genes.
RESULTS: We characterized the strategies of MGP analyses and the types and localizations of the identified mutations and showed that 13 and 11 of the analyzed genes were significantly associated with an increased BC and OC risk, respectively. The risk attributed to some of these genes (e.g., CDKN2A and PALB2 for BC) was similar to that observed for BRCA2. The analysis also showed a substantial difference in the profile of genes contributing to either BC or OC risk, including genes specifically associated with a high risk of OC but not BC (e.g., RAD51C, and RAD51D).
CONCLUSIONS: Our study provides strong statistical proof, defines the risk for many genes often considered candidates for BC/OC predisposition and excludes the role of other genes frequently analyzed in the MGPs. In the context of clinical diagnostics, the results support the knowledge-based interpretation of identified mutations.

Valvo V, Nucera C
Coding Molecular Determinants of Thyroid Cancer Development and Progression.
Endocrinol Metab Clin North Am. 2019; 48(1):37-59 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Thyroid cancer is the most common endocrine malignancy. Its incidence and mortality rates have increased for patients with advanced-stage papillary thyroid cancer. The characterization of the molecular pathways essential in thyroid cancer initiation and progression has made huge progress, underlining the role of intracellular signaling to promote clonal evolution, dedifferentiation, metastasis, and drug resistance. The discovery of genetic alterations that include mutations (BRAF, hTERT), translocations, deletions (eg, 9p), and copy-number gain (eg, 1q) has provided new biological insights with clinical applications. Understanding how molecular pathways interplay is one of the key strategies to develop new therapeutic treatments and improve prognosis.

Piskunova IS, Obukhova TN, Parovichnikova EN, et al.
Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia.
Ter Arkh. 2018; 90(7):30-37 [PubMed] Related Publications
AIM: To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol.
MATERIALS AND METHODS: The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification.
RESULTS: Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p<0.0001) and chance of recurrence (HR - 6.4; p=0.02).
CONCLUSION: Adverse prognostic factors in terms of therapeutic management provided in ALL-2009 protocol were MLL/t(11q23) and с-MYC/t(8q24) genes abnormalities. CDKN2A/9p21 and TP53/17p13 genes deletions, quantative and complex karyotype abnormalities were not prognostic factors in adult patients with Ph-negative ALL in ALL-2009 protocol use.

Bollaert E, de Rocca Serra A, Demoulin JB
The HMG box transcription factor HBP1: a cell cycle inhibitor at the crossroads of cancer signaling pathways.
Cell Mol Life Sci. 2019; 76(8):1529-1539 [PubMed] Related Publications
HMG box protein 1 (HBP1) is a transcription factor and a potent cell cycle inhibitor in normal and cancer cells. HBP1 activates or represses the expression of different cell cycle genes (such as CDKN2A, CDKN1A, and CCND1) through direct DNA binding, cofactor recruitment, chromatin remodeling, or neutralization of other transcription factors. Among these are LEF1, TCF4, and MYC in the WNT/beta-catenin pathway. HBP1 also contributes to oncogenic RAS-induced senescence and terminal cell differentiation. Collectively, these activities suggest a tumor suppressor function. However, HBP1 is not listed among frequently mutated cancer driver genes. Nevertheless, HBP1 expression is lower in several tumor types relative to matched normal tissues. Several micro-RNAs, such as miR-155, miR-17-92, and miR-29a, dampen HBP1 expression in cancer cells of various origins. The phosphatidylinositol-3 kinase (PI3K)/AKT pathway also inhibits HBP1 transcription by preventing FOXO binding to the HBP1 promoter. In addition, AKT directly phosphorylates HBP1, thereby inhibiting its transcriptional activity. Taken together, these findings place HBP1 at the center of a network of micro-RNAs and oncoproteins that control cell proliferation. In this review, we discuss our current understanding of HBP1 function in human physiology and diseases.

Meerson A, Eliraz Y, Yehuda H, et al.
Obesity impacts the regulation of miR-10b and its targets in primary breast tumors.
BMC Cancer. 2019; 19(1):86 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: Obesity increases breast cancer (BC) risk in post-menopausal women by mostly unknown molecular mechanisms which may partly be regulated by microRNAs (miRNAs).
METHODS: We isolated RNA from paired benign and malignant biopsies from 83 BC patients and determined miRNA profiles in samples from 12 women at the extremes of the BMI distribution by RNA-seq. Candidates were validated in all samples. Associations between miR-10b expression and validated target transcript levels, and effects of targeted manipulation of miR-10b levels in a primary BC cell line on proliferation and invasion potential, were explored.
RESULTS: Of the 148 miRNAs robustly expressed in breast tissues, the levels of miR-21, miR-10b, miR-451a, miR-30c, and miR-378d were significantly associated with presence of cancer. Of these, miR-10b showed a stronger down-regulation in the tumors of the obese subjects, as opposed to the lean. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53 and TRA2B, as well as tumor grade. Suppression of miR-10b levels in BT-549 primary BC-derived cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets BCL2L11, PIEZO1 and NCOR2.
CONCLUSIONS: Our findings suggest that miR-10b may be a mediator between obesity and cancer in post-menopausal women, regulating several known cancer-relevant genes. MiR-10b expression may have diagnostic and therapeutic implications for the incidence and prognosis of BC in obese women.

Jang W, Park J, Kwon A, et al.
CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.
Exp Mol Med. 2019; 51(1):4 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

Prawdzic Seńkowska A, Kiczmer P, Strzelczyk JK, et al.
Impact of HPV infection on gene expression and methylation in oral cancer patients.
J Med Microbiol. 2019; 68(3):440-445 [PubMed] Related Publications
PURPOSE: The current study aimed to examine the association between head and neck squamous cell carcinoma (HNSCC) and infection with different human papillomavirus virus (HPV) subtypes, including analysis of promoter methylation of several genes (APC, CDKN2A, MGMT, CDH1 and TIMP3) and the correlation with their mRNA expression in tumours and surgical margins.
METHODOLOGY: In 47 patients with a primary tumour of the oral cavity, HPV detection and identification of 33 subtypes was performed after previous DNA isolation using a GenoFlow HPV Array Test Kit.
RESULTS: Fifteen patients (31.92 %) were HPV [+] and the following HPV types were detected: 16 (46.67 %), 18 (6.67 %) and 43/44 (40 %). This study is the first to describe HPV 43/44 subtypes in HNSCC in a Polish population. We noted no clinical significance of HPV [+] HNSCC compared to HPV [-], however, this differed among HPV subtypes. CDKN2A promoter methylation was more frequent in HPV-16/18 patients compared to HPV43/44 patients, but there was no difference in gene expression level between HPV [+] and [-] patients.
CONCLUSION: We detected HPV infection in 31.92 % of oral cancer cases. HPV 16, along with HPV 43/44, were the most frequent subtypes. Knowledge of HPV [+] HNSCC biology may be useful in establishing the prognosis and developing novel therapies in future.

Ziai H, Alenazi A, Hearn M, et al.
The association of Bcl-xL and p53 expression with survival outcomes in oropharyngeal cancer.
Cancer Biomark. 2019; 24(2):141-151 [PubMed] Related Publications
BACKGROUND: The role of molecular biomarkers in oropharyngeal squamous cell carcinoma (OPSCC) has recently been increasingly recognized. There is conflicting evidence in the literature with regards to the prognostic value of p53 and Bcl-xL.
OBJECTIVE: The purpose of this study was to investigate the association between p53 and Bcl-xL expression profiles and survival outcomes in OPSCC.
METHODS: Patients diagnosed with OPSCC and treated with curative intent between 1998 and 2009 were included in the study. Patient demographics, disease, treatment, and oncologic outcomes were collected prospectively. A tissue microarray (TMA) from patients' biopsies or surgical specimens was retrospectively constructed. The expression levels of p53, Bcl-xL, and p16 were digitally quantified and correlated to patient survival outcomes.
RESULTS: One hundred and sixty-six patients were included (mean age 56.7 years; standard deviation (SD) ± 10.0; 78% male). High expression of Bcl-xL (p= 0.04) was significantly associated with nodal disease at presentation, and decreased overall survival (OS) (p= 0.04). Combined expression of low Bcl-xL and low p53 conferred a survival advantage in non-smokers (p= 0.04). Multivariate analysis supported smoking and p16 status as independent prognosticators for OS.
CONCLUSIONS: This study suggests that biomarker profiling using Bcl-xL and p53 levels may be of prognostic value in select patients with OPSCC.

Smal MP, Kuzhir TD, Savina NV, et al.
BER gene polymorphisms associated with key molecular events in bladder cancer.
Exp Oncol. 2018; 40(4):288-298 [PubMed] Related Publications
AIM: Base excision repair (BER) gene polymorphisms are known to play an independent role in predisposition to developing different cancers as well as to be associated with clinicopathological traits of the disease modifying its clinical outcomes. One of the underlying mechanisms is presumed to include interplay between BER gene polymorphisms and key mutational, epigenetic and chromosomal events in tumor tissues. The present study was aimed at elucidating potential gene-gene interaction and assessing their mutual effects in bladder cancer (BC).
MATERIALS AND METHODS: The earlier obtained data on genotyping patients with verified diagnosis of BC for OGG1 rs1052133 (Ser326Cys) and XRCC1 rs25487 (Arg399Gln) polymorphisms were used for this study. The tumor tissue samples from the same patients were analyzed for mutations, epigenetic variations and losses of heterozygosity in some key genes involved in divergent pathogenic pathways of BC.
RESULTS: It was shown that the OGG1 (326 codon) heterozygous genotype as well as the minor 326Cys allele can intensify a mutational response of the RAS locus in urothelial carcinomas in the total cohort of patients simultaneously decreasing the mutation rates in the PIK3CA locus in smokers. The XRCC1 (399 codon) heterozygous genotype as well as the minor 399Gln allele reduced the frequency of LOH in the PTEN and TNKS genes, but did not affect the mutational variability in any locus tested. Both polymorphisms influenced the methylation status, carriers of OGG1 326Ser/Cys or Ser/Cys+Cys/Cys genotypes demonstrating increased frequency of methylated RUNX3 and ISL1 genes whereas the similar effect of XRCC1 polymorphism concerning methylation of p16 and TIMP3 genes. When dividing the total cohort into groups based on the extent of tumor spread, the observed associations were characteristic of non-muscle invasive BC.
CONCLUSION: The BER gene polymorphisms contributed to modification of key molecular events in urothelial carcinomas. Their mutual effects mainly manifested in non-muscle invasive BC. The underlying mechanisms as well as possible clinical outcomes need to be further explored to propose novel prognostic biomarkers for BC.

Martin-Guerrero I, Salaverria I, Burkhardt B, et al.
Non-leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma.
Genes Chromosomes Cancer. 2019; 58(6):365-372 [PubMed] Related Publications
Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non-leukemic B-myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B-cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18, and 21. One B-T MPAL showed typical aberrations of T-cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN-LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2-qter affecting the ATM gene. ATM was also mutated in a T-myeloid MPAL case with additional loss at 7q21.2-q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN-LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow-up 3-10 years, median: 4.9 years). In summary, the present series of non-leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances.

Mäki-Nevala S, Valo S, Ristimäki A, et al.
DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression.
EBioMedicine. 2019; 39:280-291 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR.
METHODS: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing.
FINDINGS: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas.
INTERPRETATION: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. FUND: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Juselius Foundation, and HiLIFE.

Yao Q, Morgan GJ, Chim CS
Distinct promoter methylation profile reveals spatial epigenetic heterogeneity in 2 myeloma patients with multifocal extramedullary relapses.
Clin Epigenetics. 2018; 10(1):158 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Spatial and subclonal genetic heterogeneity in multiple myeloma (MM) have been demonstrated by sequencing of plasma cells from multi-focal regions, but studies of spatial epigenetic heterogeneity are scanty. Herein, promoter methylation status of genes implicated in disease progression (CDKN2A and SHP1) and marrow escape (CDH1, CD56, and CXCR4) was studied in two patients with multi-focal extramedullary relapses. Patient 1 developed simultaneous chest wall and duodenal plasmacytoma at relapse. While SHP1 and CDKN2A were hypermethylated in both plasmacytomas, CDH1 hypermethylation was detected only in the chest wall. In patient 2, SHP1 methylation was found in the extradural plasmacytoma but not bone marrow (BM) at diagnosis, and the circulating PCs but not the BM at relapse. As the clonality, based on sequence of the complementarity-determining region 3 (CDR3) of the immunoglobulin gene, was conserved in plasma cells at diagnosis and relapse, differential methylation of CDH1 in patient 1 and SHP1 in patient 2 was an illustration of spatial epigenetic heterogeneity. Furthermore, subclonal epigenetic heterogeneity was identified by the presence of subclonal SHP1 promoter methylation within the chest wall plasmacytoma of patient 1. In summary, our data showed distinct promoter methylation profile of plasma cells from multiple regions. This is the first report of spatial epigenetic heterogeneity in MM.

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