Gene Summary

Gene:PMS2; PMS1 homolog 2, mismatch repair system component
Aliases: MLH4, PMSL2, HNPCC4, PMS2CL
Summary:The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mismatch repair endonuclease PMS2
Source:NCBIAccessed: 15 March, 2017


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • Testis
  • Structural Homology, Protein
  • Thymine DNA Glycosylase
  • DNA Sequence Analysis
  • Peritoneal Neoplasms
  • Two-Hybrid System Techniques
  • Thyroid Cancer
  • Recombinant Proteins
  • Polymerase Chain Reaction
  • Registries
  • Sex Factors
  • Signal Transducing Adaptor Proteins
  • DNA-Binding Proteins
  • Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • Microsatellite Instability
  • Ovarian Cancer
  • Turcot Syndrome
  • DNA Repair Enzymes
  • Reproducibility of Results
  • Prostate Cancer
  • Risk Assessment
  • Young Adult
  • Pedigree
  • Sensitivity and Specificity
  • Yeasts
  • Mismatch Repair Endonuclease PMS2
  • Nuclear Proteins
  • Single-Blind Method
  • Sequence Homology, Nucleic Acid
  • MutL Protein Homolog 1
  • Chromosome 7
  • DNA Mismatch Repair
  • Tissue Array Analysis
  • Protein Structure, Tertiary
  • Retroelements
  • Western Australia
  • Skin Cancer
  • VHL
  • Societies, Medical
  • Acute Lymphocytic Leukaemia
  • Genetic Recombination
  • Pseudogenes
  • Adenosine Triphosphatases
  • Sebaceous Gland Neoplasms
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: PMS2 (cancer-related)

Kacerovska D, Drlik L, Slezakova L, et al.
Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome.
Am J Dermatopathol. 2016; 38(12):915-923 [PubMed] Related Publications
A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma. In some sebaceous lesions, squamous metaplasia, intratumoral heterogeneity, mucinous changes, and peritumoral lymphocytes as sometimes seen in sebaceous lesions in Muir-Torre syndrome were noted. Mutation analysis of the peripheral blood revealed a germline mutation c.692G>A,p.(Arg231His) in exon 9 and c.1145G>A, p.(Gly382Asp) in exon 13 of the MUTYH gene. A KRAS mutation G12C (c.34G>T, p.Gly12Cys) was detected in 1 sebaceous adenoma and a NRAS mutation Q61K (c.181C>A, p.Gln61Lys) was found in 2 other sebaceous adenomas. No germline mutations in MLH1, MSH2, MSH6 and PMS2 genes, no microsatellite instability, no aberrant methylation of MLH1 promoter, and no somatic mutations in MSH2 and MSH6 were found. An identical MUTYH germline mutation was found in the patient's daughter. Despite striking clinicopathological similarities with Muir-Torre syndrome, the molecular biologic testing confirmed the final diagnosis of MUTYH-associated polyposis.

Gelsomino F, Barbolini M, Spallanzani A, et al.
The evolving role of microsatellite instability in colorectal cancer: A review.
Cancer Treat Rev. 2016; 51:19-26 [PubMed] Related Publications
Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, et al.
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.
Oncol Rep. 2016; 36(5):2823-2835 [PubMed] Related Publications
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

Sugano K, Nakajima T, Sekine S, et al.
Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan.
Cancer Sci. 2016; 107(11):1677-1686 [PubMed] Free Access to Full Article Related Publications
Germline PMS2 gene mutations were detected by RT-PCR/direct sequencing of total RNA extracted from puromycin-treated peripheral blood lymphocytes (PBL) and multiplex ligation-dependent probe amplification (MLPA) analyses of Japanese patients with colorectal cancer (CRC) fulfilling either the revised Bethesda Guidelines or being an age at disease onset of younger than 70 years, and screened by mismatch repair protein immunohistochemistry of formalin-fixed paraffin embedded sections. Of the 501 subjects examined, 7 (1.40%) showed the downregulated expression of the PMS2 protein alone and were referred to the genetic counseling clinic. Germline PMS2 mutations were detected in 6 (85.7%), including 3 nonsense and 1 frameshift mutations by RT-PCR/direct sequencing and 2 genomic deletions by MLPA. No mutations were identified in the other MMR genes (i.e. MSH2, MLH1 and MSH6). The prevalence of the downregulated expression of the PMS2 protein alone was 1.40% among the subjects examined and IHC results predicted the presence of PMS2 germline mutations. RT-PCR from puromycin-treated PBL and MLPA may be employed as the first screening step to detect PMS2 mutations without pseudogene interference, followed by the long-range PCR/nested PCR validation using genomic DNA.

Pokharel HP, Hacker NF, Andrews L
Changing patterns of referrals and outcomes of genetic participation in gynaecological-oncology multidisciplinary care.
Aust N Z J Obstet Gynaecol. 2016; 56(6):633-638 [PubMed] Related Publications
BACKGROUND: Genetic participation in gynaecological oncology multidisciplinary team meetings (MDT) may identify the sentinel cancer in women with hereditary breast-ovarian cancer syndrome or Lynch syndrome.
AIMS: To identify the changing patterns of genetic referral from 2010 to 2014 and the outcomes of referrals through clinical MDT case review.
MATERIALS AND METHODS: Medical records of cases of gynaecological cancer presented at the MDT meetings and genetics databases were reviewed to determine the frequency and outcomes of recommendations for genetic referral between 2010 and 2014.
RESULTS: Four hundred and sixty-two women of 2523 cases reviewed were recommended for referral, increasing from 8% in 2010 to 25% in 2014. However, 167 of 462 patients (36%) had not registered with a Hereditary Cancer Clinic in NSW/ACT, including 11 women with high-grade serous ovarian cancer and seven women with abnormal MMR immunohistochemistry. Mutations were identified in 40 of 165 women (24%) undergoing breast cancer BRCA1/2 testing and in ten of 25 women (40%) who underwent MMR genetic testing. Eighty-one first- or second-degree relatives of these women have undergone predictive testing, identifying 48 mutation carriers and 33 non-carriers.
CONCLUSION: Changing indications and increased participation by a genetic consultant in the weekly MDT meeting has led to increasing genetic referrals over the last five years. Follow up of referrals needs to be addressed. With decreasing costs of genetic testing and use of readily transportable DNA collected through saliva or mouth swabs, we propose that distance should not be a barrier to this model being extended to all centres providing care to gynaecological cancer patients.

Peng HX, Xu X, Yang R, et al.
Molecular analysis of MLH1 variants in Chinese sporadic colorectal cancer patients.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
Single nucleotide polymorphisms (SNPs) in mismatch repair genes, especially in the MLH1 gene, are closely associated with susceptibility to hereditary nonpolyposis colorectal cancer. However, few relevant findings are available regarding the association between sporadic colorectal cancer (SCRC) and SNPs of MLH1 in Chinese patients. Therefore, the present study aimed to describe the pathogenic association between three important MLH1 polymorphisms and SCRC in the Chinese population. Peripheral blood samples from 156 SCRC patients and 311 healthy controls were collected. DNA was purified from peripheral blood, and the V384D, R217C, and I219V polymorphisms were evaluated using high-resolution melting analysis and direct sequencing. The association between the three important MLH1 polymorphisms and clinical pathological features of the SCRC patients was analyzed. In addition, PMS2-MLH1 protein interactions were determined by co-immunoprecipitation (Co-IP) to determine the protein functional alteration induced by these SNPs. Among the three polymorphisms, V384D was significantly associated with the risk of SCRC (OR = 31.36, P < 0.0001). The allele frequencies were 4.81 and 0.16% in the SCRC group. No association was found between SCRC and R217C, or between SCRC and I219V. Moreover, the allele frequency of R217C was significantly higher in the SCRC patients younger than 60 years than in those older than 60 years. Co-IP showed that the MLH1 R217C, V384D, and I219V variants had relative binding abilities with PMS2 of 0.59, 0.70, and 0.80, respectively, compared with the wild-type. These findings suggest that MLH1 V384D could be a promising genetic marker for susceptibility to SCRC.

Randall LM, Pothuri B
The genetic prediction of risk for gynecologic cancers.
Gynecol Oncol. 2016; 141(1):10-6 [PubMed] Related Publications
Salient to the intent of personalized medicine, hereditary cancer syndromes present significant opportunities in the treatment and prevention of some gynecologic cancers. Mutations in BRCA1, BRCA2, and DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 are important causal agents in hereditary breast and ovarian cancer (HBOC) and Lynch syndromes. Though they only account for an estimated 10-18% of ovarian, tubal, peritoneal, and endometrial cancer cases, inherited cancers are imminently preventable if mutation carriers are identified in a timely manner. Population level screening is currently impractical due to low prevalence of disease, cost of testing, and ethical issues associated with testing, so diagnosis of these mutations is limited. Being affected by one of the heritable gynecologic malignancies is a logical entry point into the genetic counseling and testing pipeline for the patient and her family members. Thus, gynecologic cancer providers are uniquely positioned to diagnose germline mutations that can inform prognosis and treatment for their patients in addition to enabling prevention for patients' cancer-unaffected blood relatives, or "previvors". The purpose of this review is to describe our current perspective on testing for and implications of heritable cancer syndromes in the women with ovarian, tubal, peritoneal, and endometrial cancers.

Tung N, Lin NU, Kidd J, et al.
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.
J Clin Oncol. 2016; 34(13):1460-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population.
METHODS: Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations.
RESULTS: Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes.
CONCLUSION: Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

Walcott FL, Patel J, Lubet R, et al.
Hereditary cancer syndromes as model systems for chemopreventive agent development.
Semin Oncol. 2016; 43(1):134-45 [PubMed] Related Publications
Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.

Chang YC, Chang JG, Liu TC, et al.
Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients.
World J Gastroenterol. 2016; 22(7):2314-25 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
AIM: To investigate the driver gene mutations associated with colorectal cancer (CRC) in the Taiwanese population.
METHODS: In this study, 103 patients with CRC were evaluated. The samples consisted of 66 men and 37 women with a median age of 59 years and an age range of 26-86 years. We used high-resolution melting analysis (HRM) and direct DNA sequencing to characterize the mutations in 13 driver genes of CRC-related pathways. The HRM assays were conducted using the LightCycler® 480 Instrument provided with the software LightCycler® 480 Gene Scanning Software Version 1.5. We also compared the clinicopathological data of CRC patients with the driver gene mutation status.
RESULTS: Of the 103 patients evaluated, 73.79% had mutations in one of the 13 driver genes. We discovered 18 novel mutations in APC, MLH1, MSH2, PMS2, SMAD4 and TP53 that have not been previously reported. Additionally, we found 16 de novo mutations in APC, BMPR1A, MLH1, MSH2, MSH6, MUTYH and PMS2 in cancerous tissues previously reported in the dbSNP database; however, these mutations could not be detected in peripheral blood cells. The APC mutation correlates with lymph node metastasis (34.69% vs 12.96%, P = 0.009) and cancer stage (34.78% vs 14.04%, P = 0.013). No association was observed between other driver gene mutations and clinicopathological features. Furthermore, having two or more driver gene mutations correlates with the degree of lymph node metastasis (42.86% vs 24.07%, P = 0.043).
CONCLUSION: Our findings confirm the importance of 13 CRC-related pathway driver genes in the development of CRC in Taiwanese patients.

Buza N, Ziai J, Hui P
Mismatch repair deficiency testing in clinical practice.
Expert Rev Mol Diagn. 2016; 16(5):591-604 [PubMed] Related Publications
Lynch syndrome, an autosomal dominant inherited disorder, is caused by inactivating mutations involving DNA mismatch repair (MMR) genes. This leads to profound genetic instability, including microsatellite instability (MSI) and increased risk for cancer development, particularly colon and endometrial malignancies. Clinical testing of tumor tissues for the presence of MMR gene deficiency is standard practice in clinical oncology, with immunohistochemistry and PCR-based microsatellite instability analysis used as screening tests to identify potential Lynch syndrome families. The ultimate diagnosis of Lynch syndrome requires documentation of mutation within one of the four MMR genes (MLH1, PMS2, MSH2 and MSH6) or EPCAM, currently achieved by comprehensive sequencing analysis of germline DNA. In this review, the genetic basis of Lynch syndrome, methodologies of MMR deficiency testing, and current diagnostic algorithms in the clinical management of Lynch syndrome, are discussed.

Liu Q, Thompson BA, Ward RL, et al.
Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.
Hum Mutat. 2016; 37(5):417-26 [PubMed] Related Publications
Lynch syndrome is the most common familial cancer condition that mainly predisposes to tumors of the colon and endometrium. Cancer susceptibility is caused by the autosomal dominant inheritance of a loss-of-function mutation or epimutation in one of the DNA mismatch repair (MMR) genes. Cancer risk assessment is often possible with nonsynonymous coding region mutations, but in many cases patients present with DNA sequence changes within noncoding regions, including the promoters, of MMR genes. The pathogenic role of promoter variants, and hence clinical significance, is unclear and this hinders the clinical management of carriers. In this review, we provide an overview of the classification of MMR gene variants, outline the laboratory assays and online resources that can be used to assess the causality of promoter variants in Lynch syndrome, and highlight some of the practical challenges of demonstrating the pathogenicity of these variants. In conclusion, we propose a guide that could be integrated into the current InSiGHT classification scheme to help determine if a MMR gene promoter variant is pathogenic.

Vierkoetter KR, Kagami LA, Ahn HJ, et al.
Loss of Mismatch Repair Protein Expression in Unselected Endometrial Adenocarcinoma Precursor Lesions.
Int J Gynecol Cancer. 2016; 26(2):228-32 [PubMed] Related Publications
OBJECTIVE: The benefit of evaluating the precursor of endometrial carcinoma, endometrial hyperplasia (intraepithelial neoplasia [EIN]), for loss of mismatch repair (MMR) protein expression and Lynch syndrome has yet to be determined. The present study aims to establish the incidence and type of loss of MMR protein expression in unselected premalignant lesions of endometrial adenocarcinoma, as well as the agreement of immunohistochemical staining in pretreatment endometrial biopsy (EMB) specimens with subsequent uterine resections.
METHODS: A retrospective review identified 112 endometrial biopsies meeting criteria for endometrial EIN. Slides made from tissue microarray blocks were evaluated using antibodies against MLH1, PMS2, MSH2, and MSH6. Cases with a deficit in MLH1 were evaluated for gene promoter hypermethylation by polymerase chain reaction analysis. Fifty-four subsequent hysterectomy specimens were retrieved and assessed for MMR protein expression.
RESULTS: Of the 112 endometrial biopsies with EIN, 4.5% (5/112) exhibited loss of MMR protein expression. The majority (4/5) demonstrated a deficit of MLH1, of which all exhibited inactivation via promoter hypermethylation. A single case displayed an absence of MSH6. Age was not significantly associated with MMR deficiency. There was no significant association between MMR status in the EMB and a subsequent diagnosis of cancer. Immunohistochemical staining in all successive hysterectomy cases was concordant with the pattern observed in the EMB specimen.
CONCLUSIONS: Sporadic hypermethylation of MLH1 seems to be the primary mechanism underlying defective MMR protein expression in EIN. Among our cohort, only 1 patient (<1%) had a mutation suggestive of a hereditary inheritance. Hence, the utility of evaluating EIN for MMR protein expression as a screen for Lynch syndrome is limited, regardless of age.

Kidambi TD, Blanco A, Van Ziffle J, Terdiman JP
Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome.
Fam Cancer. 2016; 15(2):275-80 [PubMed] Related Publications
At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.

Sijmons RH, Hofstra RM
Review: Clinical aspects of hereditary DNA Mismatch repair gene mutations.
DNA Repair (Amst). 2016; 38:155-62 [PubMed] Related Publications
Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder.

Ripperger T, Schlegelberger B
Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome.
Eur J Med Genet. 2016; 59(3):133-42 [PubMed] Related Publications
Constitutional mismatch repair deficiency (CMMRD) syndrome is one of the rare diseases associated with a high risk of cancer. Causative mutations are found in DNA mismatch repair genes PMS2, MSH6, MSH2 or MLH1 that are well known in the context of Lynch syndrome. CMMRD follows an autosomal recessive inheritance trait and is characterized by childhood brain tumors and hematological malignancies as well as gastrointestinal cancer in the second and third decades of life. There is a high risk of multiple cancers, occurring synchronously and metachronously. In general, the prognosis is poor. About one third of CMMRD patients develop hematological malignancies as primary (sometimes the only) malignancy or as secondary neoplasm. T-cell non-Hodgkin lymphomas, mainly of mediastinal origin, are the most frequent hematological malignancies. Besides malignant diseases, non-neoplastic features are frequently observed, e.g. café-au-lait spots sometimes resembling neurofibromatosis type I, hypopigmented skin lesions, numerous adenomatous polyps, multiple pilomatricomas, or impaired immunoglobulin class switch recombination. Within the present review, we summarize previously published CMMRD patients with at least one hematological malignancy, provide an overview of steps necessary to substantiate the diagnosis of CMMRD, and refer to the recent most relevant literature.

Aronson M, Gallinger S, Cohen Z, et al.
Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium.
Am J Gastroenterol. 2016; 111(2):275-84 [PubMed] Related Publications
OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.
METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.
RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.
CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

Norquist BM, Harrell MI, Brady MF, et al.
Inherited Mutations in Women With Ovarian Carcinoma.
JAMA Oncol. 2016; 2(4):482-90 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
IMPORTANCE: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.
OBJECTIVE: To determine the frequency and importance of germline mutations in cancer-associated genes in OC.
DESIGN, SETTING, AND PARTICIPANTS: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay.
MAIN OUTCOMES AND MEASURES: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status.
RESULTS: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations.
CONCLUSIONS AND RELEVANCE: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

Bernards SS, Norquist BM, Harrell MI, et al.
Genetic characterization of early onset ovarian carcinoma.
Gynecol Oncol. 2016; 140(2):221-5 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
OBJECTIVE: Ovarian carcinoma (OC) is rare in young women and the fraction of early onset OC attributable to inherited mutations in known OC genes is uncertain. We sought to characterize the fraction of OC that is heritable in women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma at forty years of age or younger.
METHODS: We sequenced germline DNA from forty-seven women diagnosed with OC at age 40 or younger ascertained through a gynecologic oncology tissue bank or referred from outside providers using BROCA, a targeted capture and massively parallel sequencing platform that can detect all mutation classes. We evaluated 11 genes associated with ovarian carcinoma (BARD1, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51D, and RAD51C) and additional candidate genes in DNA repair (ATM, BAP1, CHEK2, MRE11A, NBN, PTEN, TP53). We counted only clearly damaging mutations.
RESULTS: Damaging mutations in OC genes were identified in 13 of 47 (28%) subjects, of which 10 (77%) occurred in BRCA1 and one each occurred in BRCA2, MSH2, and RAD51D. Women with a strong family history were no more likely to have an OC gene mutation (8/17, 47%) than those without a strong family history (9/30, 30%, P=0.35). Additionally, damaging mutations in non-OC genes were identified, one in NBN and one in CHEK2.
CONCLUSIONS: A high proportion of young women with invasive OC have mutations in BRCA1, and a smaller fraction have mutations in other known OC genes. Family history was not associated with mutation status in these early onset cases.

Shikama A, Minaguchi T, Matsumoto K, et al.
Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.
Gynecol Oncol. 2016; 140(2):226-33 [PubMed] Related Publications
OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas.
METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification.
RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]).
CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

Villacis RA, Miranda PM, Gomy I, et al.
Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes.
Int J Cancer. 2016; 138(8):1928-35 [PubMed] Related Publications
In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (∼ 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency.

Wang Q
Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes.
Acta Pharmacol Sin. 2016; 37(2):143-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy.

Zhang J, Walsh MF, Wu G, et al.
Germline Mutations in Predisposition Genes in Pediatric Cancer.
N Engl J Med. 2015; 373(24):2336-46 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.
METHODS: In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).
RESULTS: Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.
CONCLUSIONS: Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).

Goodfellow PJ, Billingsley CC, Lankes HA, et al.
Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.
J Clin Oncol. 2015; 33(36):4301-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS.
PATIENTS AND METHODS: ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women.
RESULTS: Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years.
CONCLUSION: Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Olsen J, Eiholm S, Kirkeby LT, et al.
CDX2 downregulation is associated with poor differentiation and MMR deficiency in colon cancer.
Exp Mol Pathol. 2016; 100(1):59-66 [PubMed] Related Publications
BACKGROUND: Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk.
METHODS: Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2.
RESULTS: A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk.
CONCLUSION: We found that CDX2 downregulation is associated with MMR deficiency, right-sided tumors, and poor differentiation at both the mRNA and protein level. Whether CDX2 plays an active role in tumor progression in MSI/MMR-deficient tumors remains to be elucidated.

Baris HN, Barnes-Kedar I, Toledano H, et al.
Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.
Pediatr Blood Cancer. 2016; 63(3):418-27 [PubMed] Related Publications
BACKGROUND: Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1.
PROCEDURE: We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer.
RESULTS: In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified.
CONCLUSIONS: CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.

Kansal R, Li X, Shen J, et al.
An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study.
Genes Chromosomes Cancer. 2016; 55(2):131-42 [PubMed] Related Publications
A 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few café-au-lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing NF1, NF2, and RASA1 (blood), and NF2 and SMARCB1 (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T>C;p.Phe120Ser and c.3344G>A;p.Arg1115Gln, in MLH3 (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen-predicted as probably damaging, and benign, respectively. Sanger sequencing confirmed both variants in the proband, and their absence in the mother; biological father unavailable. Both biopsied tissues were negative for microsatellite instability, and expressed MLH1, MSH2, PMS2, MSH6, and MLH3 immunohistochemically. Chromosomal microarray showed a 133 kb segment copy number duplication of 14q12 region encompassing FOXG1, possibly explaining the developmental delay, but not the tumors. The presence of MLH3 variants with multiple benign neural and vascular tumors was intriguing for their possible role in the pathogenesis of these neoplasms, which were suspicious for, but not diagnostic of, constitutional MMR deficiency. However, functional assays of non-neoplastic patient-derived cells showed intact base-base MMR function. Also, no previous FOXG1-aberrant patient was reported with tumors. We now report a 3-year-old FOXG1-duplicated patient with a yet undescribed tumor syndrome with clinical features of neurofibromatosis types I and II, where several validation studies could not ascertain the significance of CES findings; further studies may elucidate precise mechanisms and diagnosis for clinical management, including tumor surveillance.

Wang J, Wen J, Yi R, et al.
High selectivity of PI3Kβ inhibitors in SETD2-mutated renal clear cell carcinoma.
J BUON. 2015 Sep-Oct; 20(5):1267-75 [PubMed] Related Publications
PURPOSE: Clear cell renal cell carcinoma (ccRCC) is characterized with frequent mutations of SETD2 gene and our purpose was to explore targeted therapy for this entity.
METHODS: By bioinformatic investigation of two major databases, the Genomics of Drug Sensitivity in Cancer (GDSC) database and The Cancer Genome Atlas (TCGA) database, we identified the selective PI3Kβ inhibitors TGX221 and AZD6482 as selective inhibitors for ccRCC with SETD2 mutations, with AZD6482 additionally targeting PIK3CA and CDK6 mutations.
RESULTS: Further investigation on AZD6482 profile revealed that mutations in RB1, KRAS, NRAS and APC contributed in drug resistance. Changes in both AZD6482-sensitive and -resistant gene sets showed limited impact on prognosis. Western blotting showed AZD6482 did not induce changes in a panel of major downstream effectors of AKT, but substantially increased PMS2 level. AZD6482 also selectively inhibited migration, invasiveness, and colony formation of ccRCC cells with SETD2 mutations. Integrative network analysis revealed complex interactions between these genes except SETD2.
CONCLUSION: AZD6482 is a novel inhibitor with high selectivity for ccRCC SETD2 mutations. Increased activity of PI3K/AKT/PMS2 could play a role in SETD2 mutated ccRCC.

Zauber P, Marotta S, Sabbath-Solitare M
Colorectal Cancers with the Uncommon Findings of KRAS Mutation and Microsatellite Instability.
Cytogenet Genome Res. 2015; 146(4):261-7 [PubMed] Related Publications
Sporadic colorectal cancers with microsatellite instability (MSI) frequently contain a mutation of the BRAF gene. Additionally, it has been shown that BRAF mutations in colorectal cancers are mutually exclusive of KRAS mutation. We evaluated 14 cases of colorectal cancer with MSI that were BRAF wild type but demonstrated a KRAS mutation. The codon 12/13 region in exon 2 of the KRAS oncogene and the codon 600 region in exon 15 of the BRAF gene were analyzed with standard PCR methods. MSI was evaluated by using the Bethesda panel of markers. The methylation status of the mismatch repair system was ascertained using the SALSA(®) MS-MLPA(®) methylation-specific DNA detection. The mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 were evaluated by immunohistochemical staining. A total of 530 colorectal cancers were studied for MSI and KRAS gene mutation. Fourteen (2.6%) cancers with both MSI and a KRAS mutation were identified, and all cancers were BRAF wild type. Methylation was present in 7 (50%), 5 demonstrated methylation of MLH1, 1 showed methylation of MGMT, and 1 showed methylation of MSH2. Four patients had simultaneous cancers, some of which showed different genetic changes. Immunohistochemical staining suggested a germ line mutation for 4 of 10 cases with complete staining information. KRAS mutation may occur with MSI in colorectal cancers with wild-type BRAF. If a mutation in KRAS co-exists with MSI, then strong methylation of the MLH1 gene is unlikely. These tumors demonstrate that a small number of colorectal cancers will develop with atypical patterns of molecular genetic changes, suggesting that a specific pattern of genetic changes may not be as crucial as the overall accumulation of changes, consistent with the 'unique tumor principle'.

Salo-Mullen EE, O'Reilly EM, Kelsen DP, et al.
Identification of germline genetic mutations in patients with pancreatic cancer.
Cancer. 2015; 121(24):4382-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC.
METHODS: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated.
RESULTS: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation).
CONCLUSIONS: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.

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