MUTYH Mutation Carriers Research Articles

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Germline mutations in pediatric cancer cohort with mixed-ancestry Mexicans.

Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.

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.

Abstract 621: Germline testing in African American women with invasive breast cancer

Abstract Background: Although African ancestry is not included in the NCCN guidelines for identifying women with invasive breast cancer who may benefit from genetic testing, African American women (AAW) are at increased risk of being diagnosed at a young age and/or with triple negative breast cancer, both factors that do meet NCCN criteria for genetic testing. Because AAW represent a frequently underserved population, we evaluated the utilization and results of germline testing of cancer predisposition genes in AAW with invasive breast cancer. Methods: 546 self-described AAW with invasive breast cancer enrolled in the Clinical Breast Care Project from 2001-2017). Eligibility status for genetic testing was assessed using the NCCN guidelines version 1.2019. In patients without clinical panel testing performed and with an available genomic DNA sample, targeted sequencing across 94 cancer predisposition genes was performed. Variants were classified as pathogenic, likely pathogenic, uncertain significance (VUS), likely benign or benign using ClinVar. Results: 60% of the patients were eligible for genetic testing of which 37% of underwent clinical testing. Within the high-risk women who pursued clinical testing, the mutation frequency was 13% and included mutations in ATM (n=2), BRCA1 (n=7), BRCA2 (n=5) and TP53 (n=1). High-risk women who were tested only in the research setting had a mutation frequency of 9% including BRCA1 (n=2) and BRCA2 (n=2) and single carriers of mutations in BLM, CHEK2, MLH1, MUTYH, PALB2, PMS2 and RECQL4. Within the 111 women who did not meet NCCN criteria, the mutation frequency was 5% with mutations in BRCA2 (n=3), PMS2 (n=1), SBHD (n=1) and TSC2 (n=1). Six women had previously unreported variants in BRCA1, BRCA2, TP53, ALK and RB1 and 29% of the women had VUS in genes including BRCA1 and BRCA2. Conclusions: Under current NCCN guidelines, the majority of AAW with invasive breast cancer were eligible for genetic testing; however, translating eligibility into pursuit of germline testing remains a challenge. For example, 33% of the high-risk women underwent clinical testing and 40% of the mutation carriers within the high-risk group were detected in the research setting. Furthermore, 5% of low-risk women, not currently eligible for genetic testing, were mutation carriers. In addition, while the majority (66%) of mutations detected were in BRCA1 or BRCA2, multi-gene testing allowed for an additional 50% of mutation carriers to be identified. Because identification of germline mutations may alter patient management and prevent secondary cancers, it is critical to identify and address barriers, such as evolving NCCN guidelines, cost, and patient preference, to testing and optimize the selection of AAW for genetic testing. The views expressed in this abstract are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. Citation Format: Leann A. Lovejoy, Seth K. Rummel, Craig D. Shriver, Rachel E. Ellsworth. Germline testing in African American women with invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 621.

Abstract 1405: Identification of high and middle penetrance pathogenic variants in patients with hereditary breast/ovarian cancer by multigene panel analysis

Abstract Background: Genetic testing for breast cancer-related genes can have implications for diagnosis, treatment, and management of breast cancer. The identification of the variants causing the disease would guide the examination and diagnosis of the at-risk relatives. The purpose of this study was to identify the frequency of pathogenic or likely pathogenic variants associated with hereditary breast and ovarian cancer in Korean patients. In this study, we conducted a multigene panel containing 23 genes with high and middle penetrance rates in hereditary breast and ovarian cancer. Methods: A multigene panel was performed on 382 patients who agreed to this study and visited the genetic counselling clinic at the National Cancer Center of Korea, between October 2016 and 2018 July. For variants classification, we examined Sanger sequencing, family history, and the clinical pathological characteristics for patients according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. We also measured the expression of alternative spliced transcripts by conducting quantitative real-time PCR (qRT-PCR) to investigate the splice donor variants interpreted with pathogenic or likely pathogenic. Results: We confirmed that 42 patients (11.00%) had 23 pathogenic or 10 likely pathogenic variants for the high and middle penetrance genes such as BRCA1, BRCA2, ATM, CHEK2, MLH1, PALB2, TP53, BRIP1 and PMS2, except for heterozygous MUTYH mutation carriers. The number of mutation careers was evaluated as follows: BRCA1 in 9 patients, BRCA2 in 18 patients, ATM in 2 patients, CHEK2 in 4 patients, MLH1 in 1 patient, PALB2 in 4 patients, TP53 in 1 patient and PMS2 in 1 patient. Two patients had 2 pathogenic or likely pathogenic variants for other genes; BRCA1/BRIP1 and BRCA2/CHEK2. All of these variants were validated by Sanger sequencing. The mRNA level of CHEK2 or PALB2 genes was further reduced in the patients with the splice donor variants compared to controls. The patients with a family history were advised to follow targeted screenings according to the National Comprehensive Cancer Network (NCCN) guidelines so that early detection of cancer and reduction of risk factors can be achieved. Conclusions: Multigene panels including high and middle penetrance rate genes will provide important information for patients with a family history of cancer. However, functional studies are needed to determine potential clinical impact of these variants. Thus, we are conducting the additional functional assays to resolve the questions for these variants (This study was supported by National Cancer Center, Korea, 1710172) Citation Format: Jin-Sun Ryu, Eun Hae Cho, Kyong-Ah Yoon, Eun-Gyeong Lee, Eun-Sook Lee, Sun-Young Kong. Identification of high and middle penetrance pathogenic variants in patients with hereditary breast/ovarian cancer by multigene panel analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1405.

Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China.

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype-phenotype correlation in mutated patients. Mutation screening of 46 unrelated probands was performed using multigene panels by next-generation sequencing. Clinical data of the index were used to assess genotype-phenotype correlations. Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

Endoscopic Phenotype of Monoallelic Carriers of MUTYH Gene Mutations in the Family of Polyposis Patients: A Prospective Study.

Almost no prospective data on endoscopy in MUTYH monoallelic carriers are available. 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. This study is a prospective cohort evaluation. 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. This is a multicenter study. 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. 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. This study was limited by the small number of patients. 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 http://links.lww.com/DCR/A862.

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.

Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200–1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.

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.

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.

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

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

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;

Common MUTYH mutations and colorectal cancer risk in multiethnic populations

MUTYH is associated with colorectal cancer (CRC) risk. We studied the frequency of MUTYH and risk of CRC in Arabs, North African and European Jews. Participants were all 593 Sephardi Moroccan Jews (232 cases, 361 controls) and all 631 Arabs (327 cases, 304 controls) recruited into a population-based study of colorectal cancer in Israel, as well as a random sample of 189 Ashkenazi Jewish cases. Two MUTYH mutations, G396D and Y179C, were studied in 1,413 individuals, with MUTYH sequence analysis in 46 cases with CRC in a sibling or adenoma. No carriers of mutations in MUTYH were identified in Ashkenazi Jews and only one in Arabs. In Sephardi Jews, 28 carriers of G396D, 25 (4.2%) heterozygotes and 3 (0.5%) homozygotes were identified. Four (0.7%) were heterozygote carriers of the Y179C mutation. Two compound heterozygous carriers of Y179C and G396D were identified. Homozygote carriers of G396D had nonsignificantly elevated risk of CRC (OR=11.0, 95% CI: 0.91-213.9, p=0.06), and combined bi-allelic carriers of G396D and Y179C had increased risk, OR=17.4, 95% CI=(1.9-316.7, p=0.009). Four of five bi-allelic carriers reported a family history of CRC. Sequencing of 46 colorectal cancer cases with family history and additional adenomas, did not identify any other non-founder mutations. MUTYH carriers of the two common founder mutations are profoundly under-represented among both Ashkenazi Jews and Arabs. The prevalence of MUTYH carriers of the common mutations is much higher in Sephardi Jews. Bi-allelic carriers of mutations in MUTYH, are associated with highly risk of colorectal cancer.

MUTYH gene variants and breast cancer in a Dutch case–control study

The MUTYH gene is involved in base excision repair. MUTYH mutations predispose to recessively inherited colorectal polyposis and cancer. Here, we evaluate an association with breast cancer (BC), following up our previous finding of an elevated BC frequency among Dutch bi-allelic MUTYH mutation carriers. A case–control study was performed comparing 1,469 incident BC patients (ORIGO cohort), 471 individuals displaying features suggesting a genetic predisposition for BC, but without a detectable BRCA1 or BRCA2 mutation (BRCAx cohort), and 1,666 controls. First, for 303 consecutive patients diagnosed before age 55 years and/or with multiple primary breast tumors, the MUTYH coding region and flanking introns were sequenced. The remaining subjects were genotyped for five coding variants, p.Tyr179Cys, p.Arg309Cys, p.Gly396Asp, p.Pro405Leu, and p.Ser515Phe, and four tagging SNPs, c.37-2487G>T, p.Val22Met, c.504+35G>A, and p.Gln338His. No bi-allelic pathogenic MUTYH mutations were identified. The pathogenic variant p.Gly396Asp and the variant of uncertain significance p.Arg309Cys occurred twice as frequently in BRCAx subjects as compared to incident BC patients and controls (p = 0.13 and p = 0.15, respectively). The likely benign variant p.Val22Met occurred less frequently in patients from the incident BC (p = 0.03) and BRCAx groups (p = 0.11), respectively, as compared to the controls. Minor allele genotypes of several MUTYH variants showed trends towards association with lobular BC histology. This extensive case–control study could not confirm previously reported associations of MUTYH variants with BC, although it was too small to exclude subtle effects on BC susceptibility.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-012-1965-0) contains supplementary material, which is available to authorized users.

Evidence for accelerated colorectal adenoma–carcinoma progression in MUTYH-associated polyposis?

Background and aimMUTYH-associated polyposis (MAP) is an autosomal recessive inherited disorder characterised by the development of polyposis in the upper and lower gastrointestinal tract and a high risk of colorectal...

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