Dataset Information

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

ABSTRACT:

Purpose

While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer.

Methods

Exome sequencing of CRC-affected cousins in a set of 47 independent extended high-risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives.

Results

A FANCM stopgain variant was observed in two CRC-affected cousin pairs, each from an independent Utah high-risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC-affected cases was observed in the two extended pedigrees.

Conclusion

A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.

SUBMITTER: Cannon-Albright LA

PROVIDER: S-EPMC7767553 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

Cannon-Albright Lisa A LA Teerlink Craig C CC Stevens Jeffrey J Snow Angela K AK Thompson Bryony A BA Bell Russell R Nguyen Kim N KN Sargent Nykole R NR Kohlmann Wendy K WK Neklason Deborah W DW Tavtigian Sean V SV

Molecular genetics & genomic medicine 20201029 12

<h4>Purpose</h4>While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer.<h4>Methods</h4>Exome sequencing of CRC-affected cousins in a set of 47 independent extende ...[more]

PMID: 33118316

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Project description:In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility.MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors.Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC.Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.

Project description:ImportanceGermline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending.ObjectivesTo assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk.Design, setting, and participantsFor the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016.Main outcomes and measuresFANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history.ResultsIn this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27).Conclusions and relevanceBased on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

Dataset Information

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

Purpose

Methods

Results

Conclusion

Publications

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

Similar Datasets

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