Gene Summary

Gene:FOXL2; forkhead box L2
Summary:This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein L2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (30)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Transcriptome
  • Forkhead Transcription Factors
  • Promoter Regions
  • Point Mutation
  • Neoplasm Recurrence, Local
  • Biomarkers, Tumor
  • Immunohistochemistry
  • Gonadoblastoma
  • Sex Cord-Gonadal Stromal Tumors
  • Staging
  • Single Nucleotide Polymorphism
  • Soft Tissue Sarcoma
  • Apoptosis
  • Neoplasm Proteins
  • Chromosome 3
  • Signal Transduction
  • Ovary
  • Primary Ovarian Insufficiency
  • Sex Determination Processes
  • Testicular Cancer
  • DNA Mutational Analysis
  • Tumor Burden
  • Ovarian Cancer
  • Base Sequence
  • Ovarian Follicle
  • Cancer Gene Expression Regulation
  • Oncogenes
  • Childhood Cancer
  • Uterine Cancer
  • Forkhead Box Protein L2
  • Ribonuclease III
  • Cell Proliferation
  • Polymerase Chain Reaction
  • DEAD-box RNA Helicases
  • Granulosa Cell Tumor
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Sertoli-Leydig Cell Tumor
  • Gene Expression Profiling
  • Uterus
  • Mutation
  • Survival Rate
  • Adolescents
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: FOXL2 (cancer-related)

Loriot Y, Necchi A, Park SH, et al.
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.
N Engl J Med. 2019; 381(4):338-348 [PubMed] Related Publications
BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (
METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified
RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with

Rosas G, Ruiz R, Araujo JM, et al.
ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer.
Crit Rev Oncol Hematol. 2019; 136:48-55 [PubMed] Related Publications
The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment.

Coelho MC, Pinto RM, Murray AW
Heterozygous mutations cause genetic instability in a yeast model of cancer evolution.
Nature. 2019; 566(7743):275-278 [PubMed] Related Publications
Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation

Freitas D, Campos D, Gomes J, et al.
O-glycans truncation modulates gastric cancer cell signaling and transcription leading to a more aggressive phenotype.
EBioMedicine. 2019; 40:349-362 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Changes in glycosylation are known to play critical roles during gastric carcinogenesis. Expression of truncated O-glycans, such as the Sialyl-Tn (STn) antigen, is a common feature shared by many cancers and is associated with cancer aggressiveness and poor-prognosis.
METHODS: Glycoengineered cell lines were used to evaluate the impact of truncated O-glycans in cancer cell biology using in vitro functional assays, transcriptomic analysis and in vivo models. Tumor patients 'samples and datasets were used for clinical translational significance evaluation.
FINDINGS: In the present study, we demonstrated that gastric cancer cells expressing truncated O-glycans display major phenotypic alterations associated with higher cell motility and cell invasion. Noteworthy, the glycoengineered cancer cells overexpressing STn resulted in tumor xenografts with less cohesive features which had a critical impact on mice survival. Furthermore, truncation of O-glycans induced activation of EGFR and ErbB2 receptors and a transcriptomic signature switch of gastric cancer cells. The disclosed top activated genes were further validated in gastric tumors, revealing that SRPX2 and RUNX1 are concomitantly overexpressed in gastric carcinomas and its expression is associated with patients' poor-survival, highlighting their prognosis potential in clinical practice.
INTERPRETATION: This study discloses novel molecular links between O-glycans truncation frequently observed in cancer and key cellular regulators with major impact in tumor progression and patients' clinical outcome.

Barbosa A, Peixoto A, Pinto P, et al.
Potential clinical applications of circulating cell-free DNA in ovarian cancer patients.
Expert Rev Mol Med. 2018; 20:e6 [PubMed] Related Publications
Circulating cell-free DNA (cfDNA) consists of small fragments of DNA that circulate freely in the bloodstream. In cancer patients, a fraction of cfDNA is derived from tumour cells, therefore containing the same genetic and epigenetic alterations, and is termed circulating cell-free tumour DNA. The potential use of cfDNA, the so-called 'liquid biopsy', as a non-invasive cancer biomarker has recently received a lot of attention. The present review will focus on studies concerning the potential clinical applications of cfDNA in ovarian cancer patients.

Ortiz IMDP, Barros-Filho MC, Dos Reis MB, et al.
Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma.
Clin Epigenetics. 2018; 10(1):144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA methylation in miRNA genes has been reported as a mechanism that may cause dysregulation of mature miRNAs and consequently impact the gene expression. This mechanism is largely unstudied in papillary thyroid carcinomas (PTC).
METHODS: To identify differentially methylated miRNA-encoding genes, we performed global methylation analysis (Illumina 450 K), integrative analysis (TCGA database), data confirmation (pyrosequencing and RT-qPCR), and functional assays.
RESULTS: Methylation analysis revealed 27 differentially methylated miRNA genes. The integrative analyses pointed out miR-21 and miR-146b as potentially regulated by methylation (hypomethylation and increased expression). DNA methylation and expression patterns of miR-21 and miR-146b were confirmed as altered, as well as seven of 452 mRNAs targets were down-expressed. The combined methylation and expression levels of miR-21 and miR-146b showed potential to discriminate malignant from benign lesions (91-96% sensitivity and 96-97% specificity). An increased expression of miR-146b due to methylation loss was detected in the TPC1 cell line. The miRNA mimic transfection highlighted putative target mRNAs.
CONCLUSIONS: The increased expression of miR-21 and miR-146b due to loss of DNA methylation in PTC resulted in the disruption of the transcription machinery and biological pathways. These miRNAs are potential diagnostic biomarkers, and these findings provide support for future development of targeted therapies.

Maués JHDS, Ribeiro HF, Pinto GR, et al.
Gastric Cancer Cell Lines Have Different
Can J Gastroenterol Hepatol. 2018; 2018:5804376 [PubMed] Free Access to Full Article Related Publications

Flórido A, Saraiva N, Cerqueira S, et al.
The manganese(III) porphyrin MnTnHex-2-PyP
Redox Biol. 2019; 20:367-378 [PubMed] Free Access to Full Article Related Publications
Manganese(III) porphyrins (MnPs) are superoxide dismutase (SOD) mimics with demonstrated beneficial effects in cancer treatment in combination with chemo- and radiotherapy regimens. Despite the ongoing clinical trials, little is known about the effect of MnPs on metastasis, being therefore essential to understand how MnPs affect this process. In the present work, the impact of the MnP MnTnHex-2-PyP

Blasco V, Pinto FM, Fernández-Atucha A, et al.
Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome.
J Assist Reprod Genet. 2019; 36(1):113-120 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: The neurokinin B (NKB)/NK
METHODS: A cross-sectional study was performed in 46 healthy women and 43 PCOS women undergoing controlled ovarian stimulation. MGCs and CCs were collected from pre-ovulatory follicles after transvaginal ultrasound-guided oocyte retrieval and the expression of the genes encoding NKB (TAC3), NK3R (TACR3), KISS1, and its receptor (KISS1R) was analyzed using real-time quantitative RT-PCR.
RESULTS: TAC3, TACR3, and KISS1 mRNA levels were decreased in MGCs and CCs of PCOS women. TAC3 positively correlated with KISS1 in MGCs of healthy women and TACR3 was positively associated with KISS1R in CCs from healthy women. These associations were not observed in PCOS women.
CONCLUSION: The NKB/NK3R and KISS1/KISS1R systems are dysregulated in MGCs and CCs of PCOS women. The lower expression of these systems in GCs could contribute to the abnormal follicle development and defective ovulation that characterize the pathogenesis of PCOS.

Zhang B, Wang L, Zhao X, et al.
Identification of Candidate Genes Associated with Chemotherapy Resistance in Ovarian Cancer.
Ann Clin Lab Sci. 2018; 48(5):573-579 [PubMed] Related Publications
Ovarian cancer is the leading cause of death due to malignant tumors in female reproductive organs. However, the lack of understanding regarding its pathogenesis brings difficulties to study it. In this study, we analyze the differently expressed genes in both GSE54388 (ovarian cancer vs. normal ovarian tissues) and GSE51373 (chemotherapy-resistant vs. chemotherapy-sensitive tissues). By intersecting the differently expressed genes, 79 genes were identified. Then, further function enrichment analysis, including GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis, was performed. Also, a protein-protein network analysis was conducted to reveal the potential relationship between genes. Finally, survival analysis was utilized to find out that FOXL2 (Forkhead Box L2), TIMP3 (TIMP Metallopeptidase Inhibitor 3), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1) may serve as biomarkers for predicting the prognosis of ovarian cancer patients.

Gupta G, Bebawy M, Pinto TJA, et al.
Role of the Tristetraprolin (Zinc Finger Protein 36 Homolog) Gene in Cancer.
Crit Rev Eukaryot Gene Expr. 2018; 28(3):217-221 [PubMed] Related Publications
Cancer is a complicated transformational progression that fiercely changes the appearance of cell physiology as well as cells' relations with adjacent tissues. Developing an oncogenic characteristic requires a wide range of modifications in a gene expression at a cellular level. This can be achieved by activation or suppression of the gene regulation pathway in a cell. Tristetraprolin (TTP or ZFP36) associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3'-untranslated regions. TTP is an attractive target for therapeutic use and diagnostic tools due to its characteristic appearance in cancer tissue alone. Thus, the illumination of TTP in diverse types of cancer might deliver additional effective remedies in the coming era for cancer patients. The objective of this review is to familiarize the reader with the TTP proteins, focus on efficient properties that endow them with their effective oncogenic potential, describe their physiological role in cancer cells, and review the unique properties of TT, and of TTP-driven cancer.

Avolio R, Järvelin AI, Mohammed S, et al.
Protein Syndesmos is a novel RNA-binding protein that regulates primary cilia formation.
Nucleic Acids Res. 2018; 46(22):12067-12086 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Syndesmos (SDOS) is a functionally poorly characterized protein that directly interacts with p53 binding protein 1 (53BP1) and regulates its recruitment to chromatin. We show here that SDOS interacts with another important cancer-linked protein, the chaperone TRAP1, associates with actively translating polyribosomes and represses translation. Moreover, we demonstrate that SDOS directly binds RNA in living cells. Combining individual gene expression profiling, nucleotide crosslinking and immunoprecipitation (iCLIP), and ribosome profiling, we discover several crucial pathways regulated post-transcriptionally by SDOS. Among them, we identify a small subset of mRNAs responsible for the biogenesis of primary cilium that have been linked to developmental and degenerative diseases, known as ciliopathies, and cancer. We discover that SDOS binds and regulates the translation of several of these mRNAs, controlling cilia development.

Mesquita FP, Pinto LC, Soares BM, et al.
Small benzothiazole molecule induces apoptosis and prevents metastasis through DNA interaction and c-MYC gene supression in diffuse-type gastric adenocarcinoma cell line.
Chem Biol Interact. 2018; 294:118-127 [PubMed] Related Publications
Chemo-resistance has been reported as a relevant barrier for the efficiency of gastric cancer treatment. Therefore, the development of effective and safe drugs for cancer chemotherapy is still a challenge. The purpose of this study was to evaluate the anticancer potential of (E)-2-(((2-(benzo[d]thiazo-2-yl)hydrazono)methyl)-4-nitrophenol) (AFN01) against gastric cancer cell lines. Our results showed promising anticancer activity against gastric cancer cells ACP-02 (IC

Zhang X, Shen D, Wang Y
Detection of the DICER1 hotspot mutation alongside immunohistochemical analysis may provide a better diagnostic measure for ovarian Sertoli-Leydig cell tumors.
Pathol Res Pract. 2018; 214(9):1370-1375 [PubMed] Related Publications
BACKGROUND: To evaluate the clinicopathological and histopathological characteristics of ovarian Sertoli-Leydig cell tumors (SLCTs) in relation to differential diagnosis, and patient prognosis.
METHODS: A review of clinical data, pathological morphology and immunohistochemical analysis of SLCTs were performed in 18 SLCTs patients. The DICER1 gene mutation was assessed in eight cases that were obtained from in-house surgical resections.
RESULTS: Among 18 SLCTs patients, three cases had well-differentiated tumors, 8 cases had moderately-differentiated tumors, and the remaining 7 cases had poorly-differentiated tumors. Among the moderately-differentiated tumors, three cases occurred coincidently with other diseases - one case occurred with endometrial carcinoma (grade I), and two cases with endometrial carcinoma of the ovary (grade 2 and grade 3). Immunohistochemical staining for α-inhibin, calretinin, and FOXL2 was positive in all the biopsies tested. The intensity of staining varied depending on the percentage of Sertoli cells and the primitive gonad interstitial composition. DICER1 mutations were detected in three of eight cases that were evaluated and were significantly more in low age range patients (P < 0.05). The initial symptoms of these three cases were sexual changes and elevation of androgen levels. The follow-up time in this study ranged from 3 to 87 months with the mean follow-up time of 29.1 months. Prognosis was generally favorable. There was no recurrence or metastasis in any patient, except for one case with recurrence of endometrial carcinoma.
CONCLUSION: The clinical presentation of SLCTs can be both varied and complex. Pathological examination is imperative for both diagnostic and prognostic grading. Immunohistochemical stain of α-inhibin, FOXL2, and calretinin and genetic testing for DICER1 mutations will be more potent for differential diagnosis.

Cheng L, Li L, Wang L, et al.
A random forest classifier predicts recurrence risk in patients with ovarian cancer.
Mol Med Rep. 2018; 18(3):3289-3297 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Ovarian cancer (OC) is associated with a poor prognosis due to difficulties in early detection. The aims of the present study were to construct a recurrence risk prediction model and to reveal important OC genes or pathways. RNA sequencing data was obtained for 307 OC samples, and the corresponding clinical data were downloaded from The Cancer Genome Atlas database. Additionally, two validation datasets, GSE44104 (20 recurrent and 40 non‑recurrent OC samples) and GSE49997 (204 OC samples), were obtained from the Gene Expression Omnibus database. Differentially expressed genes were screened using the differential expression via distance synthesis algorithm, followed by gene ontology enrichment analysis and weighted gene coexpression network analysis (WGCNA). Furthermore, subnetwork analysis was conducted for the protein‑protein interaction (PPI) network using the BioNet package. Finally, a random forest classifier was constructed based on the subnetwork nodes, and its reliability was validated using the GSE44104 and GSE49997 validation datasets. A total of 44 upregulated and 117 downregulated genes were identified in the recurrent samples. Enrichment analysis indicated that cytochrome P450 family 17 subfamily A member 1 (CYP17A1) was associated with 'positive regulation of steroid hormone biosynthetic processes'. WGCNA identified turquoise and grey modules that were significantly correlated with status and prognosis. A significant PPI subnetwork containing 16 nodes was also identified, including: Transcription factor GATA‑4; fibroblast growth factor 9; aromatase; 3β‑hydroxysteroid dehydrogenase/δ5‑4‑isomerase type 2; corticosteroid 11β‑dehydrogenase isozyme 1; CYP17A1; pituitary homeobox 2; left‑right determination factor 1; homeobox protein ARX; estrogen receptor β; steroidogenic factor 1; forkhead box protein L2; myocardin; steroidogenic acute regulatory protein mitochondrial; vesicular inhibitory amino acid transporter; and twist‑related protein 1. A random forest classifier was constructed using the subnetwork nodes as feature genes, which exhibited a 92% true positive rate when classifying recurrent and non‑recurrent OC samples. The classifying efficiency of the random forest classifier was validated using the two other independent datasets. Overall, 44 upregulated and 117 downregulated genes associated with OC recurrence were identified. Furthermore, the 16 subnetwork node genes that were identified may be important molecules in OC recurrence.

Pinto MM, Monges S, Malfatti E, et al.
Sarcomeric disorganization and nemaline bodies in muscle biopsies of patients with EXOSC3-related type 1 pontocerebellar hypoplasia.
Muscle Nerve. 2019; 59(1):137-141 [PubMed] Related Publications
INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified.
METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described.
RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies.
CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.

Hillman RT, Celestino J, Terranova C, et al.
KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.
Nat Commun. 2018; 9(1):2496 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.

Losi L, Fonda S, Saponaro S, et al.
Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers.
Int J Mol Sci. 2018; 19(6) [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively), but decreased in germ cell tumors (20%). Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (

Bini Viotti J, Loebe M, Brozzi N, et al.
Solving the mystery: Hyalinized cyst wall containing organism-like structures in a lung transplant donor.
Transpl Infect Dis. 2018; 20(5):e12940 [PubMed] Related Publications
A 59-year-old man with non-ischemic cardiomyopathy underwent orthotopic heart transplantation. The donor, a 31-year-old male declared brain dead after a gunshot wound to the head, was considered high risk due to history of incarceration, illicit drug use, and sex with a HIV-positive partner. At organ procurement, the heart, kidneys, pancreas, and liver looked grossly normal. A small right lower lobe nodule was noticed, and lung biopsy was performed. Bronchoscopy showed purulent secretions in the right lower lobe. Images from pathology are presented. Lung biopsy confirmed the presence of hyalinized cyst wall containing organism-like structures. A combination of culture, microscopic morphology, and gene sequencing was used to identify the causative organism. The patient and all other organ recipients received appropriate antifungal prophylaxis and remain asymptomatic 6 months post-transplant.

Gullo I, Oliveira P, Athelogou M, et al.
New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression.
Gastric Cancer. 2019; 22(1):77-90 [PubMed] Related Publications
BACKGROUND: Gastric cancer with lymphoid stroma (GCLS) is characterized by prominent stromal infiltration of T-lymphocytes. The aim of this study was to investigate GCLS biology through analysis of clinicopathological features, EBV infection, microsatellite instability (MSI), immune gene-expression profiling and PD-L1 status in neoplastic cells and tumor immune microenvironment.
METHODS: Twenty-four GCLSs were analyzed by RNA in situ hybridization for EBV (EBER), PCR/fragment analysis for MSI, immunohistochemistry (PD-L1, cytokeratin, CD3, CD8), co-immunofluorescence (CK/PD-L1, CD68/PD-L1), NanoString gene-expression assay for immune-related genes and PD-L1 copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group.
RESULTS: GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (p = 0.02) and better overall survival (p = 0.01). EBV+ or MSI-high phenotype was found in 66.7 and 16.7% cases, respectively. GCLSs harbored a cytotoxic T-cell-inflamed profile, particularly at the invasive front of tumors (p < 0.01) and in EBV+ cases (p = 0.01). EBV+ GCLSs, when compared to EBV- GCLSs, showed higher mRNA expression of genes related to Th1/cytotoxic and immunosuppressive biomarkers. PD-L1 protein expression, observed in neoplastic and immune stromal cells (33.3 and 91.7%, respectively), and PD-L1 amplification (18.8%) were restricted to EBV+/MSI-high tumors and correlated with high values of PD-L1 mRNA expression.
CONCLUSIONS: This study shows that GCLS has a distinctive clinico-pathological and molecular profile. Furthermore, through an in-depth study of tumor immune microenvironment-by digital analysis and mRNA expression profiling-it highlights the role of EBV infection in promoting an inflamed tumor microenvironment, with putative therapeutic implications.

Pinto F, Cárcano FM, da Silva ECA, et al.
Brachyury oncogene is a prognostic factor in high-risk testicular germ cell tumors.
Andrology. 2018; 6(4):597-604 [PubMed] Related Publications
The T-box transcription factor Brachyury has been considered a cancer-specific marker and a novel oncotarget in solid tumors. Brachyury overexpression has been described in various cancers, being associated with epithelial-mesenchymal transition, metastasis, and poor prognosis. However, its clinical association with testicular germ cell tumor is unknown. We analyzed the expression of Brachyury by immunohistochemistry in a series of well-characterized testicular germ cell tumor samples and at transcript level by in silico analysis. Additionally, we aimed to investigate the clinical significance of Brachyury in testicular germ cell tumor. Brachyury cytoplasm immunostaining was present in 89.6% (86/96) of cases with nuclear staining observed in 24% (23/96) of testicular germ cell tumor. Bioinformatics microarray expression analysis of two independent cohorts of testicular germ cell tumors showed similar results with increased levels of Brachyury in testicular germ cell tumors and metastasis compared with normal testis. Clinically, Brachyury nuclear staining was statistically associated with lower event-free survival (p = 0.04) and overall survival (p = 0.01) in intermediate/high-risk testicular germ cell tumors. Univariate analysis showed that Brachyury nuclear subcellular localization was a predictor of poor prognosis (p = 0.02), while a tendency was observed by multivariate analysis (HR: 3.56, p = 0.06). In conclusion, these results indicate that Brachyury plays an oncogenic role in testicular germ cell tumors and its subcellular localization in the nucleus may constitute a novel biomarker of poor prognosis and a putative oncotarget for intermediate/high-risk testicular germ cell tumor patients.

Guida M, Tommasi S, Strippoli S, et al.
The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale).
BMC Cancer. 2018; 18(1):552 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.
METHODS: A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m
RESULTS: We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.
CONCLUSION: This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.
TRIAL REGISTRATION: EUDRACT 2009-016487-36l ; date of registration 23 June 2010.

Lopes CAM, Mesquita M, Cunha AI, et al.
Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis.
J Cell Biol. 2018; 217(7):2353-2363 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett's esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.

Owen GI, Pinto MP, Retamal IN, et al.
Chilean Gastric Cancer Task Force: A study protocol to obtain a clinical and molecular classification of a cohort of gastric cancer patients.
Medicine (Baltimore). 2018; 97(16):e0419 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000 deaths/y. Clinical outcomes and response to "one size fits all" therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response.The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein-Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up.The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region.
TRIAL REGISTRATION: Identifier: NCT03158571, Registered on May 18, 2017.

Imperatore V, Pinto AM, Gelli E, et al.
Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma.
Eur J Hum Genet. 2018; 26(7):1026-1037 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Retinoblastoma is the most common eye cancer in children. Numerous families have been described displaying reduced penetrance and expressivity. An extensive molecular characterization of seven families led us to characterize the two main mechanisms impacting on phenotypic expression, as follows: (i) mosaicism of amorphic pathogenic variants; and (ii) parent-of-origin-effect of hypomorphic pathogenic variants. Somatic mosaicism for RB1 splicing variants (c.1960+5G>C and c.2106+2T>C), leading to a complete loss of function was demonstrated by high-depth NGS in two families. In both cases, the healthy carrier parent (one with retinoma) showed a variant frequency lower than that expected for a heterozygous individual, indicating a 56-60% mosaicism level. Previous evidences of a ~3-fold excess of RB1 maternal canonical transcript led us to hypothesize that this differential allelic expression could influence phenotypic outcome in families at risk for RB onset. Accordingly, in five families, we identified a higher tumor risk associated with paternally inherited hypomorphic pathogenic variants, namely a deletion resulting in the loss of 37 amino acids at the N-terminus (c.608-16_608del), an exonic substitution with a "leaky" splicing effect (c.1331A>G), a partially deleterious substitution (c.1981C>T) and a truncating C-terminal variant (c.2663+2T>C). The identification of these mechanisms changes the genetic/prenatal counseling and the clinical management of families, indicating a higher recurrence risk when the hypomorphic pathogenic variant is inherited from the father, and suggesting the need for second tumor surveillance in unaffected carriers at risk of developing adult-onset cancer such as osteosarcoma or leiomyosarcoma.

Wang Y, Karnezis AN, Magrill J, et al.
DICER1 hot-spot mutations in ovarian gynandroblastoma.
Histopathology. 2018; 73(2):306-313 [PubMed] Related Publications
AIMS: Gynandroblastoma is a rare ovarian sex cord-stromal tumour characterised by the presence of both male (Sertoli and/or Leydig cells) and female (granulosa cells) components. We investigated the mutational status of DICER1, FOXL2 and AKT1 genes at hot-spot regions that are known to be the key driving events in the development of Sertoli-Leydig cell tumour (SLCT), adult granulosa cell tumour (aGCT) and juvenile granulosa cell tumour (jGCT), respectively, to gain insights into the molecular pathogenesis of gynandroblastoma.
METHODS AND RESULTS: Sixteen cases of gynandroblastoma were studied. All contained SLCT or Sertoli cell tumour components. aGCT and jGCT components were identified in seven and 10 cases, respectively, with one presenting both components. Heterozygous hot-spot mutations in the RNase IIIb domain of DICER1 were discovered in three cases, including one case with heterologous mucinous elements, all of which were composed of moderately or poorly differentiated SLCT and jGCT components, and harboured the mutations in both histological components. None of the 16 cases displayed mutations at the p.C134W (c.402C→G) of FOXL2 or within the pleckstrin-homology domain of AKT1. All cases showed FOXL2 immunostaining in both male and female components.
CONCLUSION: DICER1 hot-spot mutation is the key-driving event in a subset of gynandroblastomas containing components of SLCT and jGCT. Gynandroblastomas composed of SLCT and jGCT may represent morphological variants of SLCT. The molecular basis of gynandroblastoma containing a component of aGCT is different from pure aGCT.

Paulo P, Maia S, Pinto C, et al.
Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer.
PLoS Genet. 2018; 14(4):e1007355 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified "likely pathogenic" missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.

Thorsson V, Gibbs DL, Brown SD, et al.
The Immune Landscape of Cancer.
Immunity. 2018; 48(4):812-830.e14 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

Chen H, Li C, Peng X, et al.
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.
Cell. 2018; 173(2):386-399.e12 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

Bailey MH, Tokheim C, Porta-Pardo E, et al.
Comprehensive Characterization of Cancer Driver Genes and Mutations.
Cell. 2018; 173(2):371-385.e18 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

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