Abstract
BackgroundGermline mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an as yet unquantified increased risk of colorectal cancer (CRC).MethodsWe identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases diagnosed <60 years of age from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis.ResultsWe observed 67 CRCs (mean age at diagnosis=50.2 (standard deviation [SD]=13.8) years) among 364 first- and second- degree relatives from 41 POLE families and 6 CRCs (mean age at diagnosis=39.7 (SD=6.83) years) among 69 relatives from 9 POLD1 families. We estimated risks of CRC to age 70 years (95% confidence interval [CI]) for males and females, respectively, to be: 40%(26%–57%) and 32%(20%–47%) for POLE mutation carriers; and 63%(15%–99%) and 52%(11%–99%) for POLD1 mutation carriers.ConclusionCRC risks for POLE mutation carriers are sufficiently high warranting consideration of annual colonoscopy screening and management guidelines comparable to Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed, however, clinical management recommendations could follow those suggested for POLE carriers.
Highlights
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide
Gene discovery efforts have identified several novel CRC susceptibility genes, including rare germline variants within the polymerase proofreading domains of the POLE and POLD1 genes, which are reported to be associated with CRC and polyposis.[3,4,5]
MATERIALS AND METHODS We searched in PubMed for relevant studies published before October 2016 reporting pedigree and cancer data for families with germ-line POLE or POLD1 variants that were either novel or previously observed at population frequency ≤ 0.002 according to the non-Finnish European population in the Exome Aggregation Consortium (ExAC) database,[6] given recent evidence that shows low-variant allele frequency is an important guide in determining disease-causing variants.[7]
Summary
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Identifying people at high risk of developing CRC and optimizing their screening can reduce the incidence of, and mortality from, CRC. Up to 35% of CRC cases are estimated to be attributable to genetic factors;[1] known hereditary CRC syndromes caused by highpenetrance germ-line mutations account for only 3–5% of all CRCs.[2] In recent years, gene discovery efforts have identified several novel CRC susceptibility genes, including rare germline variants within the polymerase proofreading domains of the POLE and POLD1 genes, which are reported to be associated with CRC and polyposis (referred to as polymerase proofreading–associated polyposis).[3,4,5] These novel CRC susceptibility genes are included on multigene sequencing panels for clinical testing, but the age-specific cumulative risks (penetrance) of CRC for people who carry mutations in these genes have not yet been quantified, which is an impediment to optimizing personalized clinical management. Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC)
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