Monoallelic MUTYH Mutation Research Articles

Apparition of germline mutation c.1395-1397del of MUTYH in Algerian consanguineous family with colorectal cancer

MUTYH is a glycosylase that removes adenine opposite 8-oxoguanine (OG) during base-excision repair of DNA. Variants of MUTYH defective in functional activity lead to MUTYH-associated polyposis (MAP), autosomal recessive predisposition to colorectal cancer (CRC). MAP combines clinical features with other hereditary CRC syndromes, and exhibits phenotypic overlap, particularly with Lynch syndrome (LS). To determine the impact of MUTYH mutations in colorectal adenomas and cancer susceptibility, this prospective objective screens the MUTYH gene in seventeen Eastern Algerian families with clinically suspected LS but without mismatch repair (MMR) mutations. Methods: We examined the presence of the mutations in the probands and their relatives using direct sequencing of the entire coding region of the MUTYH gene. Results: The biallelic and monoallelic pathogenic MUTYH mutations, c.1395_1397del, were discovered in a consanguineous family with CRC and gastric cancer as a novel finding in our Eastern Algerian population. Conclusion: High rates of consanguinity in Algerian population increase the risk of CRC caused by biallelic mutations in the MUTYH gene. In our families, the LS and MAP phenotypes might coexist.

Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.

Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

MUTYH-associated tumor syndrome: The other face of MAP.

MUTYH gene is involved in the base excision repair (BER) mechanism and its pathogenic alterations are associated with colorectal polyposis and cancer. MUTYH-associated polyposis (MAP) is a condition which is inherited in an autosomal recessive manner. MAP patients, beyond colorectal cancer (CRC), may develop other types of tumors, including duodenal, breast, ovarian, pancreatic, bladder and skin cancers. Carriers of biallelic MUTYH likely pathogenic/pathogenic variants exhibit a high lifetime risk of CRC, though cancer risk evidence becomes less clear when monoallelic carriers and extraintestinal tumors are considered. However, several studies recently reported an increased genetic susceptibility to cancer also for carriers of germline monoallelic MUTYH mutations. Moreover, experimental evidence highlighted the MUTYH involvement in many other biological functions. In future, MUTYH mutation carriers might benefit from new target therapies involving the use of PD-1 or KRAS inhibitors. Therefore, "MUTYH-associated tumor syndrome" might be the most appropriate term, due to the multiplicity of tumors observed in MAP patients and different biological contexts in which MUTYH acts as a "playmaker". In this Review, we will investigate the impact of germline mono- and biallelic MUTYH mutations on cancer risk, providing a proposal for clinical surveillance of mutation carriers.

P044 - Monoallelic MUTYH mutations and hereditary breast cancer - results of an epidemiologic study in Brazil

P044 - Monoallelic MUTYH mutations and hereditary breast cancer - results of an epidemiologic study in Brazil

Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation

Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic germline c.934-2A > G splice site mutation in MUTYH. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.

Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort

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.

Association of monoallelic MUTYH mutation among Egyptian patients with colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous triat that involves both environmental and genetic factors. Genetic mutations of MUTYH (p.Y179C and p.G396D) have been reported to be associated with increased risk of CRC among several ethnic populations. The aim of this work is to assess the association of the monoallelic MUTYH mutations (p.Y179C and p.G396D) with increased risk of CRC among Egyptian patients. This study included 120 unrelated CRC Egyptian patients who were compared with 100 healthy controls from the same locality. For all individuals, DNA was genotyped for MUTYH p.Y179C and MUTYH p.G396D mutations using the T-ARMS-PCR technique. The frequencies of monoallelic MUTYH mutations showed a strong association with the increased risk of CRC among Egyptian patients compared with controls (12.5 vs. 4.0%, OR=3.49, 95% CI=1.12-10.90, P=0.03). Moreover, the frequency of MUTYH p.Y179C mutation was noted to be significantly higher among CRC patients compared to controls rather than MUTYH p.G396D mutation. Interestingly, CRC patients with tumors in the right side colon showed an evidence for association with the MUTYH p.Y179C mutation compared with tumors in the left side colon (p=0.01). MUTYH p.Y179C mutation was associated with an increased risk of CRC among Egyptian patients rather than MUTYH p.G396D mutation.

Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Abstract PD7-06: Multi-gene testing in a male breast cancer cohort: Insights and unexpected results

Abstract INTRODUCTION: The role of BRCA2 and BRCA1 in male breast cancer is well established, however, there is limited data regarding the role of other genes in male breast cancer. The aim of this study was to assess the clinical characteristics and genetic testing outcomes in men diagnosed with breast cancer undergoing multi-gene testing. METHODS: Test results were reviewed for male breast cancer patients who underwent analysis of breast cancer-associated genes via multi-gene testing from March 2012 to March 2015. Panels consisted of 5-49 genes, depending on the test ordered. Clinical histories provided on test requisition forms were assessed. Statistical analysis was performed using the Wilcoxon Rank Test and the Fisher's exact test. RESULTS: Approximately 12% (33/280) of men diagnosed with breast cancer were identified to carry a pathogenic mutation/likely pathogenic variant, ∼2% (5/280) were identified to carry a moderate risk mutation (APC p.I1307K or CHEK2 p.I157T), ∼1% (2/280) were identified to carry a monoallelic MUTYH mutation, ∼18% (51/280) had a variant of unknown significance but were otherwise negative, and ∼67% (189/280) tested negative. The mutation rate was highest for BRCA2, at 7.3% (18/247 tested), followed by CHEK2, at 5.1% (10/196 tested). Of note, 3 men tested positive for multiple mutations: one man had BRCA2 and ATM mutations, one man had BRCA2 and TP53 mutations, and one man, with a clinical diagnosis of ataxia-telangiectasia, had two ATM mutations. The average age at diagnosis for mutation-positive men (62.5 years) was not significantly different from negative men (59.6 years) (p=0.269). However, the average age of diagnosis for men with CHEK2 1100delC mutations (46.0 years) was significantly lower than the average age of diagnosis for men who were otherwise positive (p=0.012). Fourteen of the mutation-positive men were found to have multiple cancers; colon polyps, melanoma, and cancers of the bladder, prostate and pancreas were reported in more than one individual. Based on the family history provided, two men who tested positive for BRCA2 mutations would not otherwise have met NCCN criteria for testing. The majority of men in this cohort with a family history of male breast cancer (10/19) tested negative for a mutation. Five mutation-positive patients were found to have a family history of male breast cancer: three with CHEK2 mutations; one with a BRCA2 and a TP53 mutation; and one with two ATM mutations. Men with CHEK2 mutations were significantly more likely to have a family history of male breast cancer compared to other positive men (p=0.020) as were men with multiple mutations (p=0.008). CONCLUSION: In this cohort of male breast cancer patients, multi-gene testing identified mutations in patients that would not previously have been identified with a single gene testing approach and allowed for identification of families with multiple mutations. Age at diagnosis and family history were not predictive of positive test results in general, although men with CHEK2 100delC mutations were diagnosed at a significantly younger age. Although 30% of this cohort was not tested for CHEK2, the CHEK2 mutation rate in the men tested was second in frequency to BRCA2, suggesting a role for CHEK2 testing in male breast cancer patients. Citation Format: Pritzlaff M, Summerour P, McFarland R, Li S, Laduca H. Multi-gene testing in a male breast cancer cohort: Insights and unexpected results. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD7-06.

Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene.

The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understandin g the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone. Of the 10 carriers of both gene mutations, 8 were diagnosed with colorectal cancer. Using a weighted cohort analysis, we estimated that risk of colorectal cancer for carriers of both a MUTYH and a MMR gene mutation was substantially higher than that for carriers of a MUTYH mutation alone [hazard ratio (HR) 21.5, 95% confidence interval (CI) 9.19-50.1; p < 0.001], but not different from that for carriers of a MMR gene mutation alone (HR 1.94, 95% CI 0.63-5.99; p = 0.25). Within the limited power of this study, there was no evidence that a monoallelic MUTYH gene mutation confers additional risk of colorectal cancer for carriers of a MMR gene mutation alone. Our finding suggests MUTYH mutation testing in MMR gene mutation carriers is not clinically informative.

Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews.

Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (≥3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty-two of the 72 adenoma subjects (30.5%) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra-intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR -5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer.

MUTYH Status and Colorectal Cancer Risk: Implication for Surveillance

MUTYH polyposis (MAP) is responsible for approximately 10 and 30 % of classical and attenuated forms of adenomatous colorectal polyposes, respectively. The underlying molecular mechanism is a biallelic germline mutation of the MUTYH gene responsible for the failure of the base excision repair (BER) DNA repair system with subsequent accumulation of somatic transversion mutations. The cumulative risk of colorectal cancer is very high in the absence of adequate care. Lifelong close colonoscopic surveillance with polypectomies is recommended. Surgery (total rather than partial colectomy) is required when polyp burden exceeds the number that could be safely managed by endoscopy and/or in case of colorectal cancer. Upper gastrointestinal endoscopy is also recommended to detect and to treat duodenal lesions. An increased risk of colorectal cancer is reported in relatives of MAP patients carrying a monoallelic MUTYH mutation. According to the opinion of the majority of experts, these individuals are therefore candidates for colonoscopic surveillance as recommended for first-degree relatives of a patient with sporadic colorectal cancer.

Abstract 14: Identification of probands with multiple mutations in cancer susceptibility genes using a multigene panel approach

Abstract The multi-gene hereditary cancer panel testing approach allows for the identification of probands carrying multiple mutations in hereditary cancer predisposition genes. The purpose of this study is to assess the frequency and phenotypes of individuals in our hereditary cancer panel cohort carrying multiple mutations in hereditary cancer predisposition genes. From March 2012 through October 2013, results were reported for 4382 individuals who underwent hereditary cancer panel testing at our laboratory. Panels included comprehensive analysis of 14-24 genes, depending on the panel ordered. Genes analyzed on each panel included both genes associated with defined hereditary cancer syndromes and genes not yet associated with a defined hereditary cancer syndrome, with moderate to high penetrance estimates. Panel results were reviewed to determine the number of probands carrying multiple pathogenic mutations or likely pathogenic variants in the genes analyzed, and retrospective test requisition form review was used to obtain clinician-reported clinical history information. Biallelic MUTYH mutation carriers were not counted as multiple mutation cases, nor were individuals carrying a monoallelic MUTYH mutation in combination with a mutation in a different gene. Nine probands (0.2%) were identified to carry two cancer-predisposing mutations. Mutations included 7 small insertions/deletions, 1 nonsense, 4 missense, 3 splicing, and 3 gross deletions. Five individuals carried two mutations in moderately-penetrant cancer susceptibility genes not associated with a defined hereditary cancer syndrome. Mutated gene combinations included CHEK2/CHEK2 (confirmed to be in trans), ATM/RAD50, ATM/CHEK2 (identified in two probands), and MRE11A/PALB2. Two individuals carried one mutation in a moderately-penetrant gene and one mutation in a highly-penetrant gene associated with a defined hereditary cancer syndrome (ATM/MSH6 and MLH1/CHEK2). The remaining two individuals carried two mutations in highly-penetrant genes (MSH6/MSH6 (phase unknown) and MSH2/MSH6). The average age at first primary cancer diagnosis was 42 years (range 16-66 years). All probands had a history of cancer, including six of the nine probands with a reported history of more than one primary cancer diagnosis. Results from this study indicate that a minority of probands undergoing hereditary cancer panel testing are identified to carry multiple mutations in cancer susceptibility genes. This data highlights the need for further research to determine the clinical implications of carrying multiple mutations in cancer susceptibility genes, particularly for those with mutations in moderately-penetrant genes. Detailed pedigree analysis, co-segregation analysis, and longitudinal follow-up will be helpful in clarifying cancer risks in these probands and the significance of multiple mutations in cancer susceptibility genes. Citation Format: Chia-Ling Gau, Holly LaDuca, Hong Lu, AJ Stuenkel, Tina Pesaran, Elaine Chen, Jill Siegfried, Sharon Mexal, Robert Hoiness, Jill Cook, John Copenhaver, Elizabeth Chao. Identification of probands with multiple mutations in cancer susceptibility genes using a multigene panel approach. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 14. doi:10.1158/1538-7445.CANSUSC14-14

Risk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.

Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines

J. Balmana1, F. Balaguer2, A. Cervantes3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Department of Medical Oncology, Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona; Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of Medical Oncology, Tumor Biology Clinic, Albert Ludwigs University, Freiburg, Germany;

French experts report on MUTYH-associated polyposis (MAP)

Recent years have been characterised by an improvement in our knowledge of genetic determinism of adenomatous polyposes and by the description in 2002 of a new entity called "MUTYH-associated polyposis" (MAP), related to biallelic mutations of this gene. Its autosomal recessive mode of inheritance contrasts with the autosomal dominant inheritance of the classical "familial adenomatous polyposis" (FAP), associated with an APC germline mutation. Although some phenotypic features may be of value to distinguish these two conditions, their clinical "spectra" largely overlap and the differential diagnosis may be difficult. The purpose of this expertise conducted under the auspices of the French Institut National du Cancer (INCa) was to assess the current state of knowledge on MUTYH-associated polyposis and to establish some recommendations in the field of molecular analysis (indications of tests and analysis strategies for affected patients and their relatives) and of clinical management based on available data in the literature, on the results from the French molecular genetics laboratories performing MUTYH analysis and on the opinions of biologists and clinicians experts (genetic counsellors and gastroenterologists). The risk of colorectal cancer among relatives carrying a monoallelic MUTYH mutation was also studied.

Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.

Risks of cancers for carriers of monoallelic MUTYH mutation with a family history of colorectal cancer

Background Several studies have shown an increased risk of colorectal and extracolonic cancers for carriers of germline MUTYH mutations inherited from both parents (biallelic mutations). Extracolonic cancer risks for carriers of a MUTYH mutation inherited from only one parent (monoallelic mutation) have not previously been estimated. Materials and methods We identified 144 families of MUTYH mutation carriers from three countries that we ascertained through population-based sources of the multi-site, international Colon Cancer Family Registry. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 2,179 of their relatives. Using Cox regression weighted to adjust for the method of ascertainment, we estimated the country-, age- and sex-specific standardized incidence ratios (SIRs) of colorectal and extracolonic cancers for monoallelic mutation carriers, compared with the general population, and corresponding age-specific cumulative risks. Results Monoallelic mutation carriers with a family history of CRC had a significantly increased incidence of CRC (SIR = 2.04; 95% confidence interval, CI = 1.56 – 2.70; P <0.001), gastric cancer (SIR = 3.24; 95% CI = 2.18 – 4.98; P <0.001), and endometrial cancer (SIR = 2.23; 95% CI = 1.13 – 4.86; P = 0.03) and a marginal increased incidence of liver cancer (SIR = 3.09; 95% CI = 1.07 – 12.25; P = 0.07) compared to the general population. The estimated cumulative risks to age 70 years based on the population cancer incidence of the United States were as follows: for CRC, 6% (95% CI = 5 – %) for men and 4% (95% CI = 3 – 6%) for women; for gastric cancer, 2% (95% CI = 1 – 3%) for men and 0.7% (95% CI = 0.5 – 1%) for women; for liver cancer, 1% (95% CI = 0.3 – 3%) for men and 0.3% (95% CI = 0.1 – 1%) for women; and for endometrial cancer, 4% (95% CI = 2 – 8%). There was no evidence of increased risks for cancer of the brain, pancreas, kidney, lung, breast or prostate. Conclusion

Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis

Whether people who inherit a mutation in MUTYH from only one parent (monoallelic mutation) are at increased risk of colorectal cancer (CRC) remains controversial. Most previous studies and meta-analyses have not found statistically significant associations but, given carriers are relatively rare, may be underpowered to detect small increased risks. We have conducted a systematic review and meta-regression analysis of previously published case-control studies to estimate the strength of association for monoallelic MUTYH mutation and CRC risk. Potential sources of heterogeneity were evaluated. We have compared the carrier frequency in cases with a family history of CRC to that of controls, as a novel and powerful design, to measure statistical evidence of an association but not the strength of association. The magnitude of the genotype-disease association, estimated from a pooled odds ratio comparing cases unselected for family history with controls, was 1.15 (95% CI = 0.98-1.36) and not substantially altered by adjustment for potential sources of heterogeneity. Monoallelic mutation carrier frequency was greater for cases ascertained due to a family history (3.3%; SE 0.9%) than for controls (1.4%; SE 0.3%) (P = 0.02). Monoallelic MUTYH mutation carriers are at increased risk of CRC but the average increase is small.

Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3'UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.