Gene Summary

Gene:MUTYH; mutY DNA glycosylase
Aliases: MYH
Summary:This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:adenine DNA glycosylase
Source:NCBIAccessed: 01 September, 2019


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

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.

  • Heterozygote
  • Genotype
  • Mosaicism
  • DNA Glycosylases
  • Microsatellite Instability
  • DNA Mismatch Repair
  • Adenocarcinoma
  • Genetic Association Studies
  • Base Sequence
  • DNA Damage
  • Single Nucleotide Polymorphism
  • Risk Assessment
  • APC
  • Genetic Testing
  • Alleles
  • Adenomatous Polyposis Coli
  • Cohort Studies
  • Phosphoric Monoester Hydrolases
  • Childhood Cancer
  • Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • DNA-Binding Proteins
  • DNA Repair Enzymes
  • Cancer Gene Expression Regulation
  • Penetrance
  • High-Throughput Nucleotide Sequencing
  • Genetic Predisposition
  • Genetic Variation
  • Case-Control Studies
  • DNA Mutational Analysis
  • Chromosome 1
  • Age of Onset
  • Germ-Line Mutation
  • Breast Cancer
  • Asian Continental Ancestry Group
  • Adolescents
  • Adenomatous Polyposis Coli Protein
  • Biomarkers, Tumor
  • DNA Repair
  • Adenoma
  • Colorectal Cancer
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: MUTYH (cancer-related)

Toboeva MK, Shelygin YA, Frolov SA, et al.
MutYH-associated polyposis.
Ter Arkh. 2019; 91(2):97-100 [PubMed] Related Publications
MutYH-associated polyposis is the only polyposis syndrome with an autosomal recessive type of inheritance, often phenotypically similar to a weakened form of familial adenomatous polyposis. For the development of the disease mutations in both alleles of the gene are required, but an increased risk of developing colorectal cancer in carriers of monoallelic mutations is noted. The diagnosis of MutYH-associated polyposis should be suspected in a patient with colorectal cancer over 45 years old on the background of polyps in the colon. The review presents modern algorithms for diagnostic and treatment of the disease.

Chen H, Wang H, Liu J, et al.
Association of the MUTYH Gln324His (CAG/CAC) variant with cervical carcinoma and HR-HPV infection in a Chinese population.
Medicine (Baltimore). 2019; 98(17):e15359 [PubMed] Related Publications
This study was performed to investigate the relationship between the MUTYH Gln324His (CAG/CAC) genotype and risk of cervical squamous cell carcinoma (CSCC) in a case-control setting. Mismatch amplification-polymerase chain reaction (MA-PCR) was applied to detect the polymorphism in 400 CSCC, 400 CIN III and 1200 control participants. The homozygous His324His (CAC/CAC) genotype of MUTYH was associated with significantly increased risk of CIN III (OR = 1.94) and CSCC (OR = 3.83). Increased risk of CIN III (OR = 1.34) and CSCC (OR = 1.97) was additionally observed with the heterozygous CAG/CAC genotype. Overall, individuals in both CAC/CAC and CAG/CAC genotype groups were at higher risk of cervical carcinoma (CINIII (OR = 1.46) and CSCC (OR = 2.34)). Within the HR-HPV infection-positive group, CAC/CAC and CAG/CAC genotypes were significantly enriched in relation to CIN III and CSCC. Moreover, we observed a positive correlation between the proportion of homozygous CAC/CAC MUTYH genotype and malignant prognostic factors of CSCC, such as cell differentiation grade and lymph node metastasis. These findings clearly highlight associations between the MUTYH Gln324His (CAG/CAC) polymorphism and susceptibility to CSCC, HR-HPV infection and specific prognostic factors, supporting the utility of this variant as an early indicator for patients at high risk of cervical carcinoma.

de Mesquita GHA, Carvalho BJ, de Almeida Medeiros KA, et al.
Intussusception reveals MUTYH-associated polyposis syndrome and colorectal cancer: a case report.
BMC Cancer. 2019; 19(1):324 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We are reporting a rare case of MUTYH-associated polyposis, a colorectal cancer hereditary syndrome, diagnosticated after an intussusception. Colorectal cancer is an important cause of cancer related mortality that can be manifested by an intussusception, a rare occurrence in adults and almost always related to tumors. Approximately 5% of colorectal cancers can be attributed to syndromes known to cause hereditary colorectal cancer, such as MUTYH-associated polyposis, autosomal genetic syndrome associated with this disease.
CASE PRESENTATION: We present the case of a 44 years old male, that sought medical consultation with a complaint of abdominal discomfort, that after five days changed its characteristics. The patient was sent to the emergency department were a CT-scan revealed intestinal sub-occlusion by ileocolic invagination. Right colectomy was carried out. The anatomic-pathological examination revealed a moderately differentiated mucinous adenocarcinoma and multiples sessile polyps, which led to the suspicion of a genetic syndrome. In the genetics analysis two mutations were observed in the MUTYH gene, and MUTYH-associated polyposis was diagnosticated.
CONCLUSION: This case demonstrates the importance of meticulous analysis of the patient examinations results to identify possible discrete alterations that can lead to improved understanding of disease.

Groves A, Gleeson M, Spigelman AD
NTHL1-associate polyposis: first Australian case report.
Fam Cancer. 2019; 18(2):179-182 [PubMed] Related Publications
While familial adenomatous polyposis accounts for approximately 1% of all colorectal cancer, the genetic cause underlying the development of multiple colonic adenomas remains unsolved in many patients. Adenomatous polyposis syndromes can be divided into: familial adenomatous polyposis, MUTYH-associated polyposis, polymerase proofreading associated polyposis and the recently described NTHL1-associated polyposis (NAP). NAP is characterised by recessive inheritance, attenuated adenomatous polyposis, colonic cancer(s) and possible extracolonic malignancies. To date, 11 cases have been reported as having germline homozygous or compound heterozygous mutations in the base excision repair gene NTHL1. Here we present a further case of a 65-year-old male with a history of adenomatous polyposis and bladder cancer, who has a previously described homozygous nonsense variant in the NTHL1 gene. This case is consistent with the emerging phenotype previously described of multiple colorectal adenomas and at least one primary tumour, adding to the small but growing body of literature about NAP.

Sokic-Milutinovic A
Appropriate Management of Attenuated Familial Adenomatous Polyposis: Report of a Case and Review of the Literature.
Dig Dis. 2019; 37(5):400-405 [PubMed] Related Publications
Hereditary polyposis syndromes in which APC gene germline mutations can lead to colorectal carcinogenesis are familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and MUTYH-associated polyposis. All 3 syndromes increase the potential for the development of colorectal cancer. AFAP is diagnosed if less than 100 adenomas are detected in the colon at presentation. AFAP is inherited in an autosomal dominant manner. We present a case of a 22-year-old female with AFAP who was treated with endoscopic polypectomy and surveilled by annual colonoscopy. Guidelines for AFAP surveillance suggest annual colonoscopy with endoscopic polypectomy in asymptomatic individuals. Indications for immediate surgery include documented or suspected cancer or significant symptoms. Preferred surgical option in AFAP is colectomy and ileo-rectal anastomosis. Surveillance of the AFAP patients should include upper GI endoscopy and duodenoscopy with random biopsies of fundic gland polyps and endoscopic resection of detected adenomas. Annual thyroid ultrasound is indicated due to increased risk for thyroid cancer. In pediatric patients tested positive for germline mutation of APC gene screening for hepatoblastoma using alpha-fetoprotein and liver ultrasound should be performed.

Aghajan Y, Malicki DM, Levy ML, Crawford JR
Atypical central neurocytoma with novel EWSR1-ATF1 fusion and MUTYH mutation detected by next-generation sequencing.
BMJ Case Rep. 2019; 12(1) [PubMed] Related Publications
We present the case of a 13-year-old boy with a very unusual periventricular atypical central neurocytoma with unique molecular features treated with subtotal surgical resection and photon intensity-modulated radiotherapy. Histological features were most consistent with atypical central neurocytoma. However, next-generation sequencing analysis revealed a novel EWSR1-ATF1 gene fusion (EWSR1-ATF1) as well as a MUTYH mutation. The EWSR1-ATF1 raised the possibility of Ewing sarcoma or angiomatoid fibrous histiocytoma, however, FLI-1 immunohistochemistry was negative. MUTYH mutations have been reported in diffuse midline paediatric glioma. The role of EWSR1-ATF1 and MUTYH mutations in central nervous system tumours is not well established. We present the first case of EWSR1-ATF1 and MUTYH mutation in a rare paediatric atypical central neurocytoma. Further studies are indicated to elucidate the consequences of these gene alterations in the context of paediatric central nervous system tumours as well as to investigate the potential role for targeted therapies.

El Hachem N, Abadie C, Longy M, et al.
Endoscopic Phenotype of Monoallelic Carriers of MUTYH Gene Mutations in the Family of Polyposis Patients: A Prospective Study.
Dis Colon Rectum. 2019; 62(4):470-475 [PubMed] Related Publications
BACKGROUND: Almost no prospective data on endoscopy in MUTYH monoallelic carriers are available.
OBJECTIVE: This study aimed to define the prevalence of colorectal and duodenal adenomas in a population of people presenting with a single mutation of the MUTYH gene and being first-degree relatives of biallelic MUTYH mutation carriers.
DESIGN: This study is a prospective cohort evaluation.
PATIENTS: Patients were first-degree relatives of a patient who had polyposis with biallelic MUTYH mutation and carrying a single gene mutation of the gene from 12 French centers.
SETTINGS: This is a multicenter study.
INTERVENTION: Detailed data on life habits (tobacco, alcohol, and nonsteroidal anti-inflammatory drugs), extraintestinal manifestations, and germline analysis were recorded. Complete endoscopic evaluation (colonoscopy and upper endoscopy) with chromoendoscopy was performed.
RESULTS: Sixty-two patients were prospectively included (34 women (55%), mean age of 54, range 30-70 years). Thirty-two patients (52%) presented with colorectal polyps at colonoscopy. Of these patients with polyps, 15 (25%) had only adenomas, 8 (13%) had only hyperplastic polyps, 1 (1%) had sessile serrated adenomas, and 8 (13%) had adenomas and/or sessile serrated adenomas. We detected, in total, 29 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 6 sessile serrated adenomas. Fourteen patients (23%) presented with a single adenoma, and 10 (16%) had 1 to 5 adenomas. No patient had more than 5 adenomas. At upper endoscopy, 3 had a limited number of fundic gland polyps; none had duodenal adenomas. The 2 main missense mutations c.1145G>A, p.Gly382Asp and c.494A>G, p.Tyr165Cys were associated with the development of colorectal adenomas/serrated polyps in these monoallelic carriers.
LIMITATIONS: This study was limited by the small number of patients.
CONCLUSIONS: This prospective study provides unique prospective data suggesting that monoallelic mutation carriers related to patients with polyposis show no colorectal polyposis and have very limited upper GI manifestations justifying an endoscopic follow-up. See Video Abstract at

Sutcliffe EG, Bartenbaker Thompson A, Stettner AR, et al.
Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.
Fam Cancer. 2019; 18(2):203-209 [PubMed] Related Publications
Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.

Fulk K, LaDuca H, Black MH, et al.
Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort.
Fam Cancer. 2019; 18(2):197-201 [PubMed] Related Publications
Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher's exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86-1.36, p = 0.21-0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.

Nunziato M, Esposito MV, Starnone F, et al.
A multi-gene panel beyond BRCA1/BRCA2 to identify new breast cancer-predisposing mutations by a picodroplet PCR followed by a next-generation sequencing strategy: a pilot study.
Anal Chim Acta. 2019; 1046:154-162 [PubMed] Related Publications
By analyzing multiple gene panels, next-generation sequencing is more effective than conventional procedures in identifying disease-related mutations that are useful for clinical decision-making. Here, we aimed to test the efficacy of an 84 genes customized-panel in BRCA1 and BRCA2 mutation-negative patients. Twenty-four patients were enrolled in this study. DNA libraries were prepared using a picodroplet PCR-based approach and sequenced with the MiSeq System. Highly putative pathogenic mutations were identified in genes other than the commonly tested BRCA1/2: 2 pathogenic mutations one in TP53 and one in MUTYH; 2 missense variants in MSH6 and ATM, respectively; 2 frameshift variants in KLLN, and ATAD2, respectively; an intronic variant in ANPEP, and 3 not functionally known variants (a frameshift variant in ATM a nonsense variant in ATM and a missense variant in NFE2L2). Our results show that this molecular screening will increase diagnostic sensitivity leading to a better risk assessment in breast cancer patients and their families. This strategy could also reveal genes that have a higher penetrance for breast and ovarian cancers by matching gene mutation with familial and clinical data, thereby increasing information about hereditary breast and ovarian cancer genetics and improving cancer prevention measures or therapeutic approaches.

Liu WQ, Dong J, Peng YX, et al.
Synonymous mutation adenomatous polyposis coliΔ486s affects exon splicing and may predispose patients to adenomatous polyposis coli/mutY DNA glycosylase mutation‑negative familial adenomatous polyposis.
Mol Med Rep. 2018; 18(6):4931-4939 [PubMed] Free Access to Full Article Related Publications
Familial adenomatous polyposis (FAP) is an autosomal dominant‑inherited colorectal cancer. Recent advances in genetics have indicated that the majority of patients with FAP carry germline mutations of the adenomatous polyposis coli (APC) and mutY DNA glycosylase (MUTYH) genes. However, a large subset of families with a history of FAP have undetectable pathogenic alterations, termed APC/MUTYH mutation‑negative FAP. To investigate the germline mutations in the APC and MUTYH genes in Chinese patients with FAP, 13 unrelated patients were enrolled. Through genetic sequencing, four known pathogenic alterations (Lys1061LysfsTer2, Glu1309AspfsTer4, Arg283Ter and Ser1196Ter) of APC and two novel disease‑associated pathogenic mutations (Tyr152Ter and Ter522Gly) in MUTYH were identified in six individuals. For samples that did not present with pathogenic alterations, the functional effects of missense, synonymous and intronic mutations were analyzed using bioinformatics tools and databases. Bioinformatics prediction suggested that the synonymous mutation Tyr486Tyr in APC (APC∆486s) was likely a disease‑causing polymorphism and may have induced the exon skipping of APC. A hybrid mini‑gene assay was performed, which confirmed that the synonymous single nucleotide polymorphism APC∆486s induced major splicing defects with skipping of exon 12 in APC. The data of the present study suggested that the synonymous polymorphism APC∆486s was a potential pathogenic alteration that predisposed APC/MUTYH mutation‑negative patients to FAP.

Martin-Morales L, Rofes P, Diaz-Rubio E, et al.
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.
PLoS One. 2018; 13(9):e0203885 [PubMed] Free Access to Full Article Related Publications
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.

Dong J, Wang X, Yu Y, et al.
Association of Base Excision Repair Gene Polymorphisms with the Response to Chemotherapy in Advanced Non-Small Cell Lung Cancer.
Chin Med J (Engl). 2018; 131(16):1904-1908 [PubMed] Free Access to Full Article Related Publications
Background: Base excision repair (BER) plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Methods: During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G, and PARP1 T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P < 0.05 was considered statistically significant.
Results: The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype (odds ratio [OR]: 5.216, 95% confidence interval [CI]: 1.568-17.352, P = 0.007), TC genotype (OR: 2.692, 95% CI: 1.007-7.198, P = 0.048), as well as the genotype of TC together with CC (OR: 3.178, 95% CI: 1.229-8.219, P = 0.017) were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGG1 C1245G gene polymorphisms and chemosensitivity.
Conclusions: The PARP1 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.

Baert-Desurmont S, Coutant S, Charbonnier F, et al.
Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes.
Eur J Hum Genet. 2018; 26(11):1597-1602 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Thanks to this strategy, we detected overlapping phenotypes (e.g., MUTYH biallelic mutations mimicking Lynch syndrome), mosaic alterations and complex SVs such as a genomic deletion involving the last BMPR1A exons and PTEN, an Alu insertion within MSH2 exon 8 and a mosaic deletion of STK11 exons 3-10. This strategy allows, in a single step, detection of all types of CRC gene alterations including SVs and provides a high disease-causing variant detection rate, thus optimizing the diagnosis of inherited CRC.

Tang L, Deng L, Bai HX, et al.
Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas.
J Neurooncol. 2018; 139(3):563-571 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.
METHODS: RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.
RESULTS: The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n = 175) than in tumors without the codeletion (n = 337) (p < 0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p < 0.001).
CONCLUSIONS: Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.

Li Q, Zhao F, Ju Y
Germline mutation of CHEK2 in neurofibromatosis 1 and 2: Two case reports.
Medicine (Baltimore). 2018; 97(23):e10894 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
RATIONALE: Neurofibromatosis, including type 1 and type 2, is inherited dominant disease that causes serious consequences. The genetic mechanism of these diseases has been described, but germline mutation of checkpoint 2 kinase gene, together with other DNA repair related genes, has not been fully elucidated in the context of neurofibromatosis.
PATIENT CONCERNS: In this article, we reported identical germline mutation of CHEK2 gene (p.R180C) in a 7-year-old Tibetan boy with NF1, and in a 12-year-old Chinese girl with NF2.
DIAGNOSES: Neurofibromatosis 1 and 2 with CHECK2 gene germline mutation.
INTERVENTIONS: Both patients underwent operation to obtain tumor tissue, and peripheral blood of their family was tested.
OUTCOMES: Identical germline mutation of CHEK2 gene (p.R180C) was detected in both patients, and germline mutations of POLE, MUTYH and ATR were also detected.
LESSONS: This is the first article to describe CHEK2 mutation in both NF1 and NF2. This article highlights a possible role of CHEK2, in association with other germline genetic mutations, in tumorigenesis of NF1 and NF2.

Kidambi TD, Goldberg D, Nussbaum R, et al.
Novel variant of unknown significance in MUTYH in a patient with MUTYH-associated polyposis: a case to reclassify.
Clin J Gastroenterol. 2018; 11(6):457-460 [PubMed] Related Publications
MUTYH-associated polyposis (MAP) is a hereditary cancer syndrome that is caused by biallelic pathogenic variants in the MUTYH gene and should be evaluated for in patients with an attenuated colonic polyposis phenotype. Monoallelic pathogenic variants in MUTYH are associated with a moderate increased risk of colorectal cancer but not with the polyposis phenotype. We present a case of a patient presenting with multiple colonic adenomatous polyps, whose germline testing revealed a heterozygous pathogenic variant in MUTYH in exon 13, c.1187G > A (p.Gly396Asp) as well as a heterozygous variant of unknown significance (VUS) in MUTYH in exon 14, c.1379T > C (p.Leu460Ser). We interpret the VUS as pathogenic in light of the patient's phenotype; the fact that the VUS was in trans with a known pathogenic variant; and because all the in silico predictors suggested, it was likely to be deleterious. This case highlights the importance of a gastroenterologist recognizing the indication for genetic testing in a patient with greater than ten adenomas, the importance of a genetic counselor in interpretation of results, and is the first report of the specific variant in the literature with clinical information to suggest that it is likely pathogenic.

Gotoh N, Saitoh T, Takahashi N, et al.
Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia.
Int J Hematol. 2018; 108(3):246-253 [PubMed] Related Publications
Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35-12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.

Yehia L, Ni Y, Sesock K, et al.
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.
PLoS Genet. 2018; 14(4):e1007352 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

Royer-Pokora B, Beier M, Brandt A, et al.
Chemotherapy and terminal skeletal muscle differentiation in WT1-mutant Wilms tumors.
Cancer Med. 2018; 7(4):1359-1368 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy-treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1-mutant Wilms tumors and analyzed up- and down-regulated genes with bioinformatic methods. Cell culture experiments were performed from primary Wilms tumors and genetic alterations in WT1 and CTNNB1 analyzed. Chemotherapy induced MYF6 165-fold and several MYL and MYH genes more than 20-fold and repressed many genes from cell cycle process networks. Viable tumor cells could be cultivated when patients received less than 8 weeks of chemotherapy but not in two cases with longer treatments. In one case, viable cells could be extracted from a lung metastasis occurring after 6 months of intensive chemotherapy and radiation. Comparison of primary tumor and metastasis cells from the same patient revealed up-regulation of RELN and TBX2, TBX4 and TBX5 genes and down-regulation of several HOXD genes. Our analyses demonstrate that >8 weeks of chemotherapy can induce terminal myogenic differentiation in WT1-mutant tumors, but this is not associated with volume reduction. The time needed for all tumor cells to achieve the terminal differentiation state needs to be evaluated. In contrast, prolonged treatments can result in genetic alterations leading to resistance.

Ciavarella M, Miccoli S, Prossomariti A, et al.
Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.
Eur J Hum Genet. 2018; 26(3):387-395 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

Takao M, Yamaguchi T, Eguchi H, et al.
Characteristics of MUTYH variants in Japanese colorectal polyposis patients.
Int J Clin Oncol. 2018; 23(3):497-503 [PubMed] Related Publications
BACKGROUND: The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis.
METHODS: After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH.
RESULTS: Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants 'pathogenic' were lacking.
CONCLUSIONS: Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

Nascimento EFR, Ribeiro ML, Magro DO, et al.
Arq Bras Cir Dig. 2017 Apr-Jun; 30(2):98-102 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: MTUYH and OGG1 genes have importance in the base excision repair systems of oxidized DNA bases. Modification of the tissue expression of these genes is related to the increased risk of developing colorectal cancer.
AIM: To evaluate the tissue expression of MUTYH and OGG1 comparing normal and neoplastic tissues of patients with sporadic colorectal cancer and to correlate it with clinical and histopathological variables.
METHOD: MUTYH and OGG1 tissue expression was quantified by RT-PCR in patients with colorectal cancer and the values were compared in normal and neoplastic tissues. MUTYH and OGG1 expression was measured and normalized to the constitutive 18S gene. The level of expression of both genes was correlated with the variables: age, gender, tumor location, size of the tumor, histological type, degree of cell differentiation, invasion depth in the intestinal wall, angiolymphatic infiltration, lymph node involvement and TNM staging.
RESULTS: Was found downregulation of both genes in neoplastic when compared to normal tissue. There was downregulation of the MUTYH in larger tumors and in patients with angiolymphatic invasion. Tumors with more advanced TNM stages (III and IV) presented downregulation of both genes when compared to those with earlier stages (I and II).
CONCLUSION: The MUTYH and OGG1 genes present downregulation in the more advanced stages of colorectal cancer.

Lawler M, Alsina D, Adams RA, et al.
Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer.
Gut. 2018; 67(1):179-193 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.
DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.
RESULTS: Fifteen critical RGs are summarised below:
CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.

Kallenberg FGJ, Latchford A, Lips NC, et al.
Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations.
Dis Colon Rectum. 2018; 61(1):58-66 [PubMed] Related Publications
BACKGROUND: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation.
OBJECTIVE: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation.
DESIGN: This was an historical cohort study.
SETTINGS: This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom.
PATIENTS: We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy.
MAIN OUTCOME MEASURES: The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas.
RESULTS: Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas.
LIMITATIONS: This study was limited by its retrospective design, selection bias, and small sample size.
CONCLUSIONS: Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at

Stoffel EM, Koeppe E, Everett J, et al.
Germline Genetic Features of Young Individuals With Colorectal Cancer.
Gastroenterology. 2018; 154(4):897-905.e1 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.
METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.
RESULTS: Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.
CONCLUSIONS: Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.

Weren RD, Ligtenberg MJ, Geurts van Kessel A, et al.
NTHL1 and MUTYH polyposis syndromes: two sides of the same coin?
J Pathol. 2018; 244(2):135-142 [PubMed] Related Publications
It is now well established that germline genomic aberrations can underlie high-penetrant familial polyposis and colorectal cancer syndromes, but a genetic cause has not yet been found for the major proportion of patients with polyposis. Since next-generation sequencing has become widely accessible, several novel, but rare, high-penetrant risk factors for adenomatous polyposis have been identified, all operating in pathways responsible for genomic maintenance and DNA repair. One of these is the base excision repair pathway. In addition to the well-established role of the DNA glycosylase gene MUTYH, biallelic mutations in which predispose to MUTYH-associated polyposis, a second DNA glycosylase gene, NTHL1, has recently been associated with adenomatous polyposis and a high colorectal cancer risk. Both recessive polyposis syndromes are associated with increased risks for several other cancer types as well, but the spectrum of benign and malignant tumours in individuals with biallelic NTHL1 mutations was shown to be broader; hence the name NTHL1-associated tumour syndrome. Colorectal tumours encountered in patients with these syndromes show unique, clearly distinct mutational signatures that may facilitate the identification of these syndromes. On the basis of the prevalence of pathogenic MUTYH and NTHL1 variants in the normal population, we estimate that the frequency of the novel NTHL1-associated tumour syndrome is five times lower than that of MUTYH-associated polyposis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Sourrouille I, Lefèvre JH, Shields C, et al.
Surveillance of Duodenal Polyposis in Familial Adenomatous Polyposis: Should the Spigelman Score Be Modified?
Dis Colon Rectum. 2017; 60(11):1137-1146 [PubMed] Related Publications
BACKGROUND: Duodenal polyposis is a manifestation of adenomatous polyposis that predisposes to duodenal or ampullary adenocarcinoma. Duodenal polyposis is monitored by upper GI endoscopies and may require iterative resections and prophylactic radical surgical treatment when malignancy is threatening.
OBJECTIVE: The purpose of this study was to evaluate severity scoring for surveillance and treatment in a large series of duodenal polyposis.
DESIGN: From 1982 to 2014, every patient surveyed by upper GI endoscopies for duodenal polyposis was included.
SETTINGS: The study was conducted at a single tertiary care center.
PATIENTS: We performed 1912 upper GI endoscopies in 437 patients (median = 3; interquartile range, 2-6 endoscopies).
MAIN OUTCOME MEASURES: Conservative treatment was performed in 103 patients (159 endoscopic and 17 surgical resections), whereas radical surgical treatment (Whipple procedure or duodenectomy) was required in 52 (median age, 47.5 y; range, 43.0-57.3 y) because of high-grade dysplasia or unresectable lesions.
RESULTS: Genes involved were APC (n = 274; 62.7%) and MUTYH (n = 21; 4.8%). First upper GI endoscopies (median age, 32 y; range, 21-44 y) revealed duodenal polyposis in 190 (43.5%). Rates of low-grade dysplasia, high-grade dysplasia, and duodenal or ampulary adenocarcinoma at 5 years were 65% (range, 61.7%-66.9%), 12.1% (range, 10.3%-13.9%), and 2.4% (range, 1.5%-3.3%), whereas 10-year rates were 75.8% (range, 73.1%-78.5%), 20.8% (range, 18.2%-23.4%), and 5.4% (range, 3.8%-7.0%). The rate of ampullary abnormalities rose during surveillance from 18.3% at the first upper GI endoscopies to 47.4% at the fourth. Predictive factors for high-grade dysplasia were age at first upper GI endoscopy, type and age of colorectal surgery, Spigelman score, presence of an ampullary abnormality, and number of endoscopic treatments. In multivariate analysis, only age at first upper GI endoscopy and presence of an ampullary abnormality were independent predictive factors. Histologic analysis after radical surgical treatment showed high-grade dysplasia in 30 patients and duodenal or ampulary adenocarcinoma in 11 (4 patients had lymph node involvement).
LIMITATIONS: The study was limited by its retrospective analysis of a prospective database.
CONCLUSIONS: More than 20% of patients developed high-grade dysplasia with duodenal polyposis after 10 years. Iterative endoscopic resections allowed extended control, but surgery remained necessary in 12% of the patients and happened too late in many cases; 20% of those operated had developed duodenal or ampulary adenocarcinoma, whereas 8% exhibited malignancy with lymph node involvement. The trigger for prophylactic surgery required a more accurate predictive score leading to closer endoscopic surveillance. Modifying the Spigelman score by accounting for ampullary abnormalities should be considered as a means to increase compliance with closer endoscopic follow-up in high-risk patients. See Video Abstract at

Thomas LE, Hurley JJ, Meuser E, et al.
Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and
Clin Cancer Res. 2017; 23(21):6721-6732 [PubMed] Related Publications

Chaffee KG, Oberg AL, McWilliams RR, et al.
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.
Genet Med. 2018; 20(1):119-127 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
PurposePanel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germ-line mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history.MethodsWe sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for familial pancreatic cancer (FPC), while the remaining were familial, but not FPC.ResultsThirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2.ConclusionMultiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status and will inform genetic risk counseling for families.

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