Gene Summary

Gene:PMS1; PMS1 homolog 1, mismatch repair system component
Aliases: MLH2, PMSL1, hPMS1, HNPCC3
Summary:This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:PMS1 protein homolog 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (12)

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.

  • Nuclear Proteins
  • Colorectal Cancer
  • DNA Repair
  • Germ-Line Mutation
  • Carrier Proteins
  • MutS Homolog 2 Protein
  • Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • Species Specificity
  • Proteins
  • Single-Stranded Conformational Polymorphism
  • DNA Repair Enzymes
  • Base Pair Mismatch
  • Neoplasm Proteins
  • Transcription Factors
  • p53 Protein
  • Rectum
  • Chromosome 2
  • Mismatch Repair Endonuclease PMS2
  • Research
  • Polymerase Chain Reaction
  • Adenosine Triphosphatases
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • WT1
  • Sex Factors
  • Receptors, Progesterone
  • Sequence Homology
  • MutL Protein Homolog 1
  • Phenotype
  • Transfection
  • MutL Proteins
  • Promoter Regions
  • Saccharomyces cerevisiae Proteins
  • Pedigree
  • Skin Cancer
  • Urinary System Cancers
  • Signal Transducing Adaptor Proteins
  • Stomach Cancer
  • Mutation
  • Sequence Homology
  • Risk Factors
  • Sequence Homology, Nucleic Acid
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: PMS1 (cancer-related)

Roncati L
Microsatellite Instability Predicts Response to Anti-PD1 Immunotherapy in Metastatic Melanoma.
Acta Dermatovenerol Croat. 2018; 26(4):341-343 [PubMed] Related Publications
Dear Editor, Immune-checkpoint blockade is a type of passive immunotherapy aimed at enhancing preexisting anti-tumor responses of the organism, blocking self-tolerance molecular interactions between T-lymphocytes and neoplastic cells (1,2). Despite a significant increase in progression-free survival, a large proportion of patients affected by metastatic melanoma do not show durable responses even after appropriate diagnostic categorization and shared therapeutic choices (3-9). Therefore, predictive biomarkers of clinical response are urgently needed, and predictive immunohistochemistry (IHC) meets these requirements. Strong evidence suggests that DNA mismatch repair (MMR) deficiency is a frequent condition in malignant melanoma, as well as in other tumors (10). As is known, DNA MMR is a safeguard system for the detection and repair of DNA errors, which can randomly occur in the phase of DNA replication inside the cell. In humans, seven DNA MMR proteins (Mlh1, Mlh3, Msh2, Msh3, Msh6, Pms1, and Pms2) work in a coordinated and sequential manner to repair DNA mismatches. When this system is defective, the cell accumulates a series of replication errors in terms of new microsatellites; therefore, a condition of genetic hypermutability and microsatellite instability (MSI) takes place inside the cell itself (11). For this reason, my working group has started to search for MMR protein deficiency in melanoma biopsies from patients of both sexes and of all ages with metastatic spread, correlating the data with the response to pembrolizumab, the well-known anti-programmed cell death protein 1 (PD1) human monoclonal immunoglobulin G4, capable of blocking the interaction between PD1, the surface receptor of activated T-lymphocytes, and its ligand, the programmed death-ligand 1 (PD-L1), favoring melanoma cell attack by T-lymphocytes (1) rather than its depression (12). PD-L1 is highly expressed in about half of all melanomas and thus the role of PD1 in melanoma immune evasion is now well established (13). Surprisingly, the best therapeutic results to pembrolizumab, in terms of progression-free survival and overall survival, occur precisely in those patients, approximately 7% in my database, affected by deficient MMR (dMMR) melanomas. In particular, the most important benefits to pembrolizumab-based treatment have occurred in a female patient, who developed a subungual melanoma in the second finger of the left hand at the age of 41 years, together with lymph node metastases to ipsilateral axilla at the onset. The patient was promptly submitted to amputation of the first phalanx and emptying of the axillary cable. The primary tumor was a vertical growth phase melanoma with a Breslow's depth of 1.4 mm; three mitotic figures for 1 mm2 were ascertained. There was no evidence of ulceration, regression, microsatellitosis, or lymphocytic infiltration; moreover, the surgical margins tested free of disease. Further molecular analyses did not show rearrangements in B-RAF and C-KIT genes. After four years, metastases appeared in the brain and ileum; however, at present the patient is still alive and in complete pembrolizumab response with progression-free survival and overall survival of 956 days and 2546 days, respectively. The tumor was afterwards identified as a dMMR melanoma for an exclusive loss of Msh6 expression on IHC (Figure 1). This finding is in line with the fact that the U.S. Food and Drug Administration has approved the use of pembrolizumab in 2017 for unresectable or metastatic solid tumors with MMR deficiency (14). In conclusion, dMMR melanoma seems to be a particular subset of disease that can be identified with high sensibility and specificity by predictive IHC as a complete loss of one or more DNA MMR proteins and that deserves targeted therapy.

Arulananda S, Thapa B, Walkiewicz M, et al.
Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma.
J Thorac Oncol. 2018; 13(10):1588-1594 [PubMed] Related Publications
INTRODUCTION: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins.
DESIGN: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI).
RESULTS: Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining.
CONCLUSION: In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.

Nakamura K, Nakayama K, Minamoto T, et al.
Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report.
Int J Mol Sci. 2018; 19(4) [PubMed] Free Access to Full Article Related Publications
Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (

Liccardo R, De Rosa M, Izzo P, Duraturo F
Novel MSH2 splice-site mutation in a young patient with Lynch syndrome.
Mol Med Rep. 2018; 17(5):6942-6946 [PubMed] Free Access to Full Article Related Publications
Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3. The mutations identified in MMR genes are point mutations or large rearrangements. The point mutations are certainly pathogenetic whether they determine formation of truncated protein. The mutations that arise in splice sites are classified as 'likely pathogenic' variants. In the present study, a novel splicing mutation was identified, (named c.212‑1g>a), in the MSH2 gene. This novel mutation in the consensus splice site of MSH2 exon 2 leads to the loss of the canonical splice site, without skipping in‑frame of exon 2; also with the formation of 2 aberrant transcripts, due to the activation of novel splice sites in exon 2. This mutation was identified in a young patient who developed colon cancer at the age of 26 years and their belongs to family that met the 'Revised Amsterdam Criteria'. The present study provided insight into the molecular mechanism determining the pathogenicity of this novel MSH2 mutation and it reaffirms the importance of genetic testing in LS.

Javid M, Sasanakietkul T, Nicolson NG, et al.
DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.
World J Surg. 2018; 42(2):358-366 [PubMed] Related Publications
BACKGROUND: Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis.
METHODS: MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests.
RESULTS: Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p < 0.05 two-tailed). Rate of LOH, a measure of genomic instability, was higher in PMS2-deficient PTCs (median 3 and 1, respectively; U = 26, p < 0.05 two-tailed). No correlation was noted between MMR deficiency and clinical characteristics.
CONCLUSIONS: MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

Zhao C, Li S, Zhao M, et al.
Prognostic values of DNA mismatch repair genes in ovarian cancer patients treated with platinum-based chemotherapy.
Arch Gynecol Obstet. 2018; 297(1):153-159 [PubMed] Free Access to Full Article Related Publications
PURPOSE: DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR has been reported as a prognostic marker in certain cancers; however, the results are controversial. Therefore, identification of the prognostic value of MMR genes in ovarian cancer based on a large sample size is pivotal.
METHODS: In the current study, we systemically investigated the prognostic roles of seven MMR genes, MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2, in ovarian cancer patients treated with platinum-based chemotherapy through "The Kaplan-Meier plotter" (KM plotter) database, which contains gene expression data and survival information of ovarian cancer patients.
RESULTS: Among seven MMR genes, high mRNA levels of MSH6, MLH1 and PMS2 were significantly associated with a better overall survival for all ovarian cancer patients treated with platinum-based chemotherapy, especially in late-stage and poor-differentiated ovarian cancer patients. Increased MSH6 and PMS2 mRNA expression was correlated with a favorable overall survival in serous ovarian cancer patients.
CONCLUSIONS: Our results indicate that sufficient MMR system is associated with an improved survival in ovarian cancer treated with platinum-based chemotherapy. MMR gene may be a potential prognosis predictor in ovarian cancer.

Micu BV, Andercou O, Vesa SC, et al.
The prognostic role of microsatellite instability in colorectal cancer patients.
Ann Ital Chir. 2017; 6:425-432 [PubMed] Related Publications
BACKGROUND: Data from the literature regarding the prognostic role of DNA mismatch repair system (MMR) in colorectal cancer are still controversial.
AIM: The aim of the study was to identify the prognostic role of different phenotypic, clinical and pathological characteristics in microsatellite unstable vs. microsatellite stable colorectal cancer in terms of survival and disease free interval.
METHODS: We conducted a retrospective study that included a total of 103 patients who underwent curative surgery for colorectal cancer. Immunohistochemistry testing revealed MLH1, MLH2, MLH6, PMS2 genes and mutations of the BRAF gene. We identified three groups of patients: patients with colorectal tumors with MSI produced by hypermethylation, (MLH1/BRAF+) group, patients with microsatellite instable tumours produced by genetic mutations MSI groupb(MLH1, MLH2, MLH6, PMS2) and patients with microsatellite stable tumours (MSS).
RESULTS: The study shows that: MSI tumours (MLH1/BRAF+) group occur more frequently in women (p=0.05), on the right side of the colon (p=0.001). The 5-year survival rate was higher in patients with MSI tumours (MLH1/BRAF+) group than in those with microsatellite stable tumours, the differences were not statistically significant ; relapse rate was higher in patients with MSI tumors than in those with MSI tumours (MLH1/BRAF+) group (p=0.03) or with MSS tumors (p=0.004).
CONCLUSIONS: The identification of microsatellite unstable colorectal tumours is an important molecular marker with role in recognition subgroups of patients with different phenotypic characteristics, survival and relapse rates.
KEY WORDS: Colorectal cancer, Mismatch repair genes, Prognostic role.

Nguyen KA, Syed JS, Espenschied CR, et al.
Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test.
Cancer. 2017; 123(22):4363-4371 [PubMed] Related Publications
BACKGROUND: Panel testing has been recently introduced to evaluate hereditary cancer; however, limited information is available regarding its use in kidney cancer.
METHODS: The authors retrospectively reviewed test results and clinical data from patients who underwent targeted multigene panel testing of up to 19 genes associated with hereditary kidney cancer from 2013 to 2016. The frequency of positive (mutation/variant likely pathogenic), inconclusive (variant of unknown significance), and negative results was evaluated. A logistic regression analysis evaluated predictive factors for a positive test.
RESULTS: Patients (n = 1235) had a median age at diagnosis of 46 years, which was significantly younger than the US population of individuals with kidney cancer (P < .0001). Overall, 6.1%, 75.5%, and 18.4% of individuals had positive, negative, and inconclusive results, respectively. The most commonly altered genes included folliculin (FLCN) and fumarate hydratase (FH), which were altered in 1.8% and 1.3% of patients, respectively. Tuberous Sclerosis Complex 2 (TSC2), mesenchymal epithelial transition factor proto-oncogene (MET), and PMS1 homolog 2 (PMS2) had the highest rates of variants of unknown significance, which were identified in 2.7%, 2.2%, and 1.7% of patients, respectively. Early age of onset was the only factor that was identified as predictive of a positive test on multivariate analysis (odds ratio, 0.975; P = .0052) and may be the only identifying characteristic of low-penetrant syndromes, such as those associated with MITF (melanogenesis-associated transcription factor) mutations, which do not have singular histology or a family history of kidney cancer.
CONCLUSIONS: Panel tests may be particularly useful for patients who lack distinguishing clinical characteristics of known hereditary kidney cancer syndromes. The current results support the use of early age of onset for genetic counseling and/or testing. Cancer 2017;123:4363-71. © 2017 American Cancer Society.

Spetsotaki KN, Tsiambas E, Stamatelopoulos A, et al.
DNA mismatch repair deficiency in lung and oral cavity carcinomas: the role of histogenetic origin.
J BUON. 2017 May-Jun; 22(3):606-609 [PubMed] Related Publications
DNA mismatch repair system (DNA MMR) is a crucial genetic mechanism for DNA homeostasis in prokaryotic and eukaryotic cells. During DNA replication and also recombination, point intra-nucleotide errors including base deletion, insertion, and mis-incorporation happen. These raised abnormalities in the newly synthesized DNA strand could affect negatively the stability of the molecule and the function of the corresponding genes. DNA MMR proteins prevent these errors by recognizing and repairing them, securing directly the normal anatomy of the DNA double strand and indirectly the expression of the genes. Specific genomic alterations - mutations, loss of heterozygosity (LOH), or promoter hypermethylation - regarding the MMR genes (human homologues) hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2 modify negatively their expression leading to loss of their function in repairing the corresponding base to base errors. The result known as microsatellite instability (MSI) was initially recognized in colonic carcinoma, especially in its inherited aspect - the Lynch syndrome -, the most common form of hereditary colon carcinoma. Since then, acquired deficiencies in specific DNA MMR genes have been detected in a broad spectrum of malignancies including different anatomic regions and histologies such as stomach, prostate, esophageal, endometrial, lung and head & neck. In the current special review we explored the role of DNA MMR deficiency in lung and oral cavity carcinomas in order to identify similarities and differences regarding the corresponding genes alterations.

Bhattacharya P, Patel TN
Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics.
Hematology. 2018; 23(2):77-82 [PubMed] Related Publications
OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies.
METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto-oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease. To prevent the deleterious effects of mutations and to protect the genomic integrity, our system possesses multiple repair mechanisms. DNA Mismatch Repair (MMR) and Direct Reversal of Damage (DRD) are two repair mechanisms which help in removal of faulty base pairs and alkyl adduct formation respectively to avoid long term effects of toxicity, tumorigenesis and mutagenesis. There are nine major MMR genes - MutS homolog (MSH2, MSH3, MSH4, MSH5, MSH6), MutL homolog (MLH1, MLH3), human post-meiotic segregation genes (PMS1, PMS2), and three major damage reversal genes - O
RESULTS: Any malfunction in DNA repair machinery can cause microsatellite instability (MSI), a form of genomic abnormality with hyper mutable repeats that is directly associated with cancer. Microsatellites are short, repetitive sequences, non-randomly distributed and localized in 3'-UTR (Untranslated Region), introns, coding regions and promoters. Besides MSI, evidence on promoter hypermethylation of selected repair genes also points toward a prominent reason for cancer initiation and progression.
CONCLUSION: The presence of specific microsatellite marker hyper-mutability and consistent promoter hypermethylation in leukemia or lymphoma can be considered as a part of routine diagnostic test in clinical laboratories.

Betti M, Casalone E, Ferrante D, et al.
Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.
Cancer Lett. 2017; 405:38-45 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

Najdawi F, Crook A, Maidens J, et al.
Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy.
Pathology. 2017; 49(5):457-464 [PubMed] Related Publications
Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.

Romaniuk А, Lyndin M, Smiyanov V, et al.
Primary multiple tumor with affection of the thyroid gland, uterus, urinary bladder, mammary gland and other organs.
Pathol Res Pract. 2017; 213(5):574-579 [PubMed] Related Publications
BACKGROUND: Nowadays multiple primary tumor is characterized by growth and development of two or more tumors in one patient. The total world sickness rate ranges from 1% to 37%. The presence of four or more tumors in one patient is rare case and presented as casuistry.
CASE PRESENTATION: We showed a case of multiple primary tumor with metahronic lesion of the thyroid, uterus and breast, followed by synchronous benign tumors of the subcutaneous fat, urinary bladder and gallbladder were considered. The development of all malignant tumors in all cases was accompanied by the presence of benign precancerous processes. Analysis of neoplasia histology shows the predominance of poorly differentiated forms of cancers in women with increased aggressiveness of cancerous tissue in each subsequent case and the growth of metastatic ability. The influence of heredity on the tumors progress is confirmed by immunohistochemical characteristics of cancer cells. Steroid-sensitive tissue of the uterus and breast in both cases didn't express ER and PR, in all cases the tissue had overexpression of Ki-67, p53, bax and bcl-2 receptors. The results of DNA testing for determination the Lynch syndrome revealed the presence of microsatellite instability in genetic material. The results of studies revealed the absence of mutations in these genes (MLH1, MSH2 and MSH6). Despite the negative results of the study, it doesn't exclude the possibility of Lynch syndrome for 100%, and its presence may be caused by the mutations of other genes (PMS1, PMS2 and MLH3), responsible for DNA repair. Unfortunately there wasn't any opportunity to study their mutations.
CONCLUSIONS: While studying the anamnesis of life and disease of women it was revealed that she had multiple primary tumor with lesions of the breast, urinary bladder, thyroid, uterus and other organs. This study shows that neoplastic tissue in all cases had high rates of cell proliferation, their antiapoptotic stability, expression of prognostically unfavorable-receptors, and absence of favorable prognostic markers. Histological study revealed high rates of malignant neoplastic tissue. It indicates to the existence of common mechanisms of malignant tumors and their genetic predisposition that can be clearly observed in many generations of patient.

Ghanipour L, Jirström K, Sundström M, et al.
Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer.
Eur J Surg Oncol. 2017; 43(2):311-321 [PubMed] Related Publications
BACKGROUND: Microsatellite instability arises due to defect mismatch repair (MMR) and occurs in 10-20% of sporadic colorectal cancer. The purpose was to investigate correlations between defect MMR, prognosis and heredity for colorectal cancer in first-degree relatives.
MATERIAL AND METHODS: Tumour tissues from 318 patients consecutively operated for colorectal cancer were analysed for immunohistochemical expression of MLH1, MSH2 and MSH6 on tissue microarrays. Information on KRAS and BRAF mutation status was available for selected cases.
RESULTS: Forty-seven (15%) tumours displayed MSI. No correlation was seen between patients exhibiting MSI in the tumour and heredity (p = 0.789). Patients with proximal colon cancer and MSI had an improved cancer-specific survival (p = 0.006) and prolonged time to recurrence (p = 0.037). In a multivariate analysis including MSI status, gender, CEA, vascular and neural invasion, patients with MSS and proximal colon cancer had an impaired cancer-specific survival compared with patients with MSI (HR, 4.32; CI, 1.46-12.78). The same prognostic information was also seen in distal colon cancer; no recurrences seen in the eight patients with stages II and III distal colon cancer and MSI, but the difference was not statistically significant.
CONCLUSION: No correlation between MSI and heredity for colorectal cancer in first-degree relatives was seen. Patients with MSI tumours had improved survival.

Carneiro da Silva F, Ferreira JR, Torrezan GT, et al.
Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.
PLoS One. 2015; 10(10):e0139753 [PubMed] Free Access to Full Article Related Publications
Lynch syndrome (LS) accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.

Ghafouri-Fard S, Fardaei M, Lankarani KB, Miryounesi M
Segregation of a novel MLH1 mutation in an Iranian Lynch syndrome family.
Gene. 2015; 570(2):304-5 [PubMed] Related Publications
Lynch syndrome is an autosomal dominant disorder caused by germline mutations in mismatch repair (MMR) genes. The main feature of this disorder is an early onset of hereditary colorectal cancer in addition to other cancers arising from different tissues. Here, we report an Iranian family with several members affected with Lynch syndrome related cancers. Exome sequencing with focus on 14 genes related with hereditary colorectal cancer has shown a novel mutation in exon 19 of MLH1 gene (c.2133delC, p.Trp712Gly fs*71). This mutation is located in a region coding for the functional domain for the interaction with MLH3/PMS1/PMS2. As some clinical aspects of the disorder have been shown to be associated with certain mutations, identification of causative mutation in each family has implications for surveillance protocols.

Liu Y, Zhang X, Jia J, et al.
Correlation between polymorphisms in DNA mismatch repair genes and the risk of primary hepatocellular carcinoma for the Han population in northern China.
Scand J Gastroenterol. 2015; 50(11):1404-10 [PubMed] Related Publications
PURPOSE: This study investigated correlations between polymorphisms in DNA mismatch repair (MMR) genes and the risk of primary hepatocellular carcinoma (PHC).
METHODS: Single nucleotide polymorphisms (SNPs) in the DNA MMR genes MLH3 (rs175080), PMS1 (rs5742933), PMS2 (rs1059060), MSH3 (rs26279), MSH5 (rs1150793, rs2075789) and MSH6 (rs1042821) were detected using the SNaPshot method in 250 PHC cases and in 308 patients without PHC in the Han population in northern China.
RESULTS: The AA genotype in MLH3 (rs175080) increased the risk of PHC (odds ratio [OR] = 3.424; 95% confidence interval [CI]: 1.097-10.689). The AG and GG genotypes in MSH3 (rs26279) increased the risk of PHC (OR: 1.644 and 3.300; 95% CI: 1.112-2.428 and 1.765-6.168, respectively). The AA genotype in MSH5 (rs2075789) increased the risk of PHC (OR: 9.229; 95% CI: 1.174-72.535). The CT genotype in MSH6 (rs1042821) reduced the risk of PHC (OR: 0.629; 95% CI: 0.428-0.924).
CONCLUSIONS: Our study suggests that polymorphisms in MLH3 (rs175080), MSH3 (rs26279), MSH5 (rs2075789) and MSH6 (rs1042821) may be independent risk factors for PHC.

Fang M, Pak ML, Chamberlain L, et al.
The CREB Coactivator CRTC2 Is a Lymphoma Tumor Suppressor that Preserves Genome Integrity through Transcription of DNA Mismatch Repair Genes.
Cell Rep. 2015; 11(9):1350-7 [PubMed] Free Access to Full Article Related Publications
The CREB-regulated transcription coactivator CRTC2 stimulates CREB target gene expression and has a well-established role in modulating glucose and lipid metabolism. Here, we find, unexpectedly, that loss of CRTC2, as well as CREB1 and its coactivator CREB-binding protein (CBP), results in a deficiency in DNA mismatch repair (MMR) and a resultant increased mutation frequency. We show that CRTC2, CREB1, and CBP are transcriptional activators of well-established MMR genes, including EXO1, MSH6, PMS1, and POLD2. Mining of expression profiling databases and analysis of patient samples reveal that CRTC2 and its target MMR genes are downregulated in specific T cell lymphoma subtypes, which are microsatellite unstable. The levels of acetylated histone H3 on the CRTC2 promoter are significantly reduced in lymphoma in comparison to normal tissue, explaining the decreased CRTC2 expression. Our results establish a role for CRTC2 as a lymphoma tumor suppressor gene that preserves genome integrity by stimulating transcription of MMR genes.

Belloni E, Veronesi G, Rotta L, et al.
Whole exome sequencing identifies driver mutations in asymptomatic computed tomography-detected lung cancers with normal karyotype.
Cancer Genet. 2015; 208(4):152-5 [PubMed] Related Publications
The efficacy of curative surgery for lung cancer could be largely improved by non-invasive screening programs, which can detect the disease at early stages. We previously showed that 18% of screening-identified lung cancers demonstrate a normal karyotype and, following high-density genome scanning, can be subdivided into samples with 1) numerous; 2) none; and 3) few copy number alterations. Whole exome sequencing was applied to the two normal karyotype, screening-detected lung cancers, constituting group 2, as well as normal controls. We identified mutations in both tumors, including KEAP1 (commonly mutated in lung cancers) in one, and TP53, PMS1, and MSH3 (well-characterized DNA-repair genes) in the other. The two normal karyotype screening-detected lung tumors displayed a typical lung cancer mutational profile that only next generation sequencing could reveal, which offered an additional contribution to the over-diagnosis bias concept hypothesized within lung cancer screening programs.

Sønderstrup IM, Nygård SB, Poulsen TS, et al.
Topoisomerase-1 and -2A gene copy numbers are elevated in mismatch repair-proficient colorectal cancers.
Mol Oncol. 2015; 9(6):1207-17 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Topoisomerase 1 (TOP1) and 2A (TOP2A) are potential predictive biomarkers for irinotecan and anthracycline treatment, respectively, in colorectal cancer (CRC), and we have recently reported a high frequency of gene gain of the TOP1 and TOP2A genes in CRC. Furthermore, Mismatch Repair (MMR) subtypes of CRC have been associated with benefit from adjuvant chemotherapy of primary CRC. Given the involvement of the topoisomerase enzymes in DNA replication and repair, we raised the hypothesis that an association may exist between TOP gene copy numbers and MMR proficiency/deficiency in CRC.
MATERIAL AND METHODS: Test cohort: FISH analysis with an in-house TOP1/CEN20 probe mix and a commercially available TOP2A/CEN17 (Dako, Glostrup, Denmark) probe mix was performed on archival formalin fixed paraffin embedded (FFPE) tissue samples from 18 patients with proficient MMR (pMMR) CRC and 18 patients with deficient MMR (dMMR) CRC. TOP1 and TOP2A gene copy numbers and their ratios per nucleus were correlated with MMR status using the Mann-Whitney test. Validation cohort: FFPE samples from 154 patients with primary stage III CRC (originally included in the RANX05 study) were classified according to MMR status by immunohistochemical analysis using validated antibodies for MLH1, MLH2, MSH6 and PMS2, and information on TOP1, CEN20, TOP2A and CEN17 status was previously published for this cohort.
RESULTS: The observed TOP1 gene copy numbers in the 36 CRC test cohort were significantly greater (p < 0.01) in the pMMR subgroup (mean: 3.84, SD: 2.03) than in the dMMR subgroup (mean: 1.50, SD: 0.12). Similarly, the TOP2A copy numbers were significantly greater (p < 0.01) in the pMMR subgroup (mean: 1.99, SD: 0.52) than in the dMMR subgroup (mean: 1.52, SD: 0.10). These findings were confirmed in the validation cohort, where in the pMMR subgroup 51% had ≥2 extra TOP1 copies per cell, while all tumors classified as dMMR had diploid TOP1 status and mean TOP2A copy numbers were 2.30 (SD: 1.36) and 1.80 (SD: 0.31) (p = 0.01) in the pMMR subgroup vs. dMMR subgroup, respectively.
DISCUSSION AND CONCLUSION: Our results show that TOP1 and TOP2A gene copy numbers are increased in the pMMR subgroup. We propose that this preference may reflect a selective pressure to gain and/or maintain the gained extra copies of topoisomerase genes whose products are required to cope with high replication stress present in the pMMR tumors, thereby providing a survival advantage selectively in pMMR tumors. Future studies should test this concept and explore potential differences between pMMR and dMMR tumors in response to Top1 and Top2 inhibitors.

Svec J, Schwarzová L, Janošíková B, et al.
Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.
Int J Clin Exp Pathol. 2014; 7(8):5196-202 [PubMed] Free Access to Full Article Related Publications
Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points out the importance of sebaceous neoplasia, especially sebaceous adenocarcinoma, as cutaneous markers of MTS for timely implementation of cancer screening programs.

Stark AM, Doukas A, Hugo HH, et al.
Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.
Neurol Res. 2015; 37(2):95-105 [PubMed] Related Publications
OBJECTIVES: Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma.
METHODS: Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival.
RESULTS: (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (P<0.001) but not with survival. (2) PCR revealed two patients with increasing expression of MLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation.
DISCUSSION: Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

Alvarado-Bachmann R, Smith A, Gundara JS, et al.
The incidence of mismatch repair gene defects in colorectal liver metastases.
Mol Med Rep. 2014; 10(2):1003-6 [PubMed] Related Publications
Knowledge of the molecular biology of primary colorectal cancer (CRC) has improved in recent years, and one reason for this is the identification of microsatellite instability (MSI), which occurs in up to 15% of sporadic CRC. However, less is known regarding the processes involved in colorectal liver metastases (CRLM). Increasing numbers of patients with CRLM are suitable for curative resection, so the identification of molecular markers may improve patient selection. The aim of the present study was to characterise the incidence of MSI in resected CRLM. Fifty‑one sequentially resected CRLM specimens were selected. Clinicopathologic data was collated and immunohistochemistry for MLH1 and MSH2 was performed on paraffin sections of the CRLM specimens. The association between abnormal staining and the clinicopathological data was examined. The median age of the subjects in the current study was 65 years, the average number of CRLM was 2 and the median overall survival time was 42.1 months post liver resection. None of the 50 resected specimens demonstrated abnormal staining for MLH1 or MSH2. Compared with the previously reported incidence of MSI in primary CRC, the low incidence of MSI in the current cohort of CRLM precludes its use as a marker for use in making clinical decisions regarding this condition.

Adamkov M, Furjelová M, Horáček J, et al.
Relationship of mismatch repair proteins and survivin in colon polyps and carcinomas.
Acta Histochem. 2014; 116(6):1007-14 [PubMed] Related Publications
Mismatch repair genes (MMR) play an essential role in DNA repair. MMR mutations predominantly in MLH1, MSH2, MSH6, PMS2, and rarely in PMS1, may cause the production of abnormally short or inactivated proteins. The antiapoptotic protein survivin functions in the inhibition of apoptosis, regulation of cell division and also enhances angiogenesis. Both MMRP and survivin are considered to be powerful prognostic parameters. This study was designed to determine the relationship between MMRP and survivin in colon lesions. The study included 113 cases of colon carcinoma and 51 cases of colon polyps. Survivin expression and MMRP status were assessed by immunohistochemistry. In each section, expression, intensity of immunostaining and percentage of labeled cells were analyzed. In carcinomas, immunoreaction was detected in 100/113 cases for MLH1 (88.5%), 112/113 cases for MSH2 (99.1%), 110/113 cases for MSH6 (97.3%), and 103/113 cases for PMS2 (91.2%). Survivin was shown in 47/113 cases (41.6%). The statistical analysis confirmed a significant correlation between the expression of MMRP and survivin in the assessed parameters. All 51 polyp samples were positive for MLH1, MSH2, MSH6 and PMS2. Only 8 of those (15.7%) were positive for survivin. Statistically significant differences were observed between the expression of MMRP and survivin. In conclusion, this study revealed that MMRP may suppress the antiapoptotic function of survivin through p53 inactivation of its promoter in grade 1 and grade 2 colon carcinomas.

Lazarev I, Leibovitch L, Czeiger D, et al.
Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency.
In Vivo. 2014 May-Jun; 28(3):349-54 [PubMed] Related Publications
UNLABELLED: While sporadic cases of colorectal cancer (CRC) most commonly arise via the well-characterized chromosomal instability pathway (CIN), most other cases develop via a serrated neoplasia pathway (CIMP), in which methylation of CpG islands results in silencing of DNA nucleotide mismatch repair (MMR)-related genes, and a high level of microsatellite instability (MSI). MSI-high tumors typically show proximal location, mucinous histology, poor differentiation, and lymphocytic infiltration. Cell-free circulating DNA (CFD) may become elevated in CRC patients compared to healthy individuals. Because of these biological differences, we hypothesized that compared to MMR-proficient tumors MMR-deficient CRCs may produce higher CFD blood levels.
PATIENTS AND METHODS: Forty-one patients with newly-diagnosed CRC from all stages were studied for MMR-proficiency status, and CFD and carcinoembryonic antigen (CEA) blood levels. MMR proficiency was evaluated in formalin-fixed, paraffin-embedded tissues by immunohistochemistry (IHC) for MLH1/MSH2. CFD plasma levels were measured with SYBR gold nucleic acid gel staining on fluorometry. MMR-proficiency status was studied by clinicopathological parameters, CFD and CEA blood levels.
RESULTS: Tumors were MMR-proficient, and -deficient in 16 patients (39%), and 25 patients (61%), respectively. The mean age of MMR-deficient patients was approximately 10 years higher than that of MMR-proficient patients (61.2±8.4 years versus 71.9±9.7 years, p=0.07). MMR-deficient tumors were more often proximally-located, (p=0.018). The mean CFD plasma levels in MMR-proficient, and MMR-deficient patients were 795±431 ng/ml, and 906±494 ng/ml, respectively (p=0.68). The mean CEA serum levels in MMR-proficient and MMR-deficient patients were 10.4±17.6 μg/l, and 15±48 μg/l, respectively (p=0.46).
CONCLUSION: Compared to MMR-proficient CRCs, MMR-deficient tumors occurred in older patients, and were more commonly proximally-located. Despite the presence of distinct biological and histopathological characteristics, both tumor types produced similar CFD blood levels.

Sameer AS, Nissar S, Fatima K
Mismatch repair pathway: molecules, functions, and role in colorectal carcinogenesis.
Eur J Cancer Prev. 2014; 23(4):246-57 [PubMed] Related Publications
The microsatellite instability (MSI) pathway is one of the important mutational pathways that play a critical role in colorectal carcinogenesis. About 15% of colorectal cancers (CRCs) are characterized by MSI. MSI tumors usually arise because of a genetic defect in mismatch repair (MMR) genes, one of the main DNA-repairing systems. MMR is a highly conserved biological pathway that plays a key role in maintaining genomic stability by correcting the base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Mutations in at least five pivotal genes of MMR, namely, in those encoding mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), mutS homolog 6 (MSH6), postmeiotic segregation increased 1 (PMS1), and postmeiotic segregation, increased 2 (PMS2) have been found in CRC, highlighting the importance of understanding the basic structure and functions of the essential molecules that make up the MMR system. In this review, we have attempted to focus on this aspect, that is, the role that MMR molecules play in CRC carcinogenesis.

Castéra L, Krieger S, Rousselin A, et al.
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes.
Eur J Hum Genet. 2014; 22(11):1305-13 [PubMed] Free Access to Full Article Related Publications
To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC.

Li H, Wawrose JS, Gooding WE, et al.
Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection.
Mol Cancer Res. 2014; 12(4):571-82 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. The increasing amount of genomic information on human tumors and cell lines provides more biologic data to design preclinical studies. We and others previously reported whole-exome sequencing data of 106 HNSCC primary tumors. In 2012, high-throughput genomic data and pharmacologic profiling of anticancer drugs of hundreds of cancer cell lines were reported. Here, we compared the genomic data of 39 HNSCC cell lines with the genomic findings in 106 HNSCC tumors. Amplification of eight genes (PIK3CA, EGFR, CCND2, KDM5A, ERBB2, PMS1, FGFR1, and WHSCIL1) and deletion of five genes (CDKN2A, SMAD4, NOTCH2, NRAS, and TRIM33) were found in both HNSCC cell lines and tumors. Seventeen genes were only mutated in HNSCC cell lines (>10%), suggesting that these mutations may arise through immortalization in tissue culture. Conversely, 11 genes were only mutated in >10% of human HNSCC tumors. Several mutant genes in the EGF receptor (EGFR) pathway are shared both in cell lines and in tumors. Pharmacologic profiling of eight anticancer agents in six HNSCC cell lines suggested that PIK3CA mutation may serve as a predictive biomarker for the drugs targeting the EGFR/PI3K pathway. These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.
IMPLICATIONS: These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.

Xiao X, Melton DW, Gourley C
Mismatch repair deficiency in ovarian cancer -- molecular characteristics and clinical implications.
Gynecol Oncol. 2014; 132(2):506-12 [PubMed] Related Publications
DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.

Chong IY, Cunningham D, Barber LJ, et al.
The genomic landscape of oesophagogastric junctional adenocarcinoma.
J Pathol. 2013; 231(3):301-10 [PubMed] Related Publications
The incidence of oesophagogastric junctional (OGJ) adenocarcinoma is rising rapidly in western countries, in contrast to the declining frequency of distal gastric carcinoma. Treatment options for adenocarcinomas involving the oesophagogastric junction are limited and the overall prognosis is extremely poor. To determine the genomic landscape of OGJ adenocarcinoma, exomes of eight tumours and matched germline DNA were subjected to massively parallel DNA sequencing. Microsatellite instability was observed in three tumours which coincided with an elevated number of somatic mutations. In total, 117 genes were identified that had predicted coding alterations in more than one tumour. Potentially actionable coding mutations were identified in 67 of these genes, including those in CR2, HGF , FGFR4, and ESRRB. Twenty-nine genes harbouring somatic coding mutations and copy number changes in the MSS OGJ dataset are also known to be altered with similar predicted functional consequence in other tumour types. Compared with the published mutational profile of gastric cancers, 49% (57/117) of recurrently mutated genes were unique to OGJ tumours. TP53, SYNE1, and ARID1A were amongst the most frequently mutated genes in a larger OGJ cohort. Our study provides an insight into the mutational landscape of OGJ adenocarcinomas and confirms that this is a highly mutated and heterogeneous disease. Furthermore, we have uncovered somatic mutations in therapeutically relevant genes which may represent candidate drug targets.

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