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. 2018 Aug;20(8):890-895.
doi: 10.1038/gim.2017.185. Epub 2017 Nov 9.

Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1

Daniel D Buchanan  1   2   3 , Jenna R Stewart  4 , Mark Clendenning  4 , Christophe Rosty  4   5   6 , Khalid Mahmood  4   7 , Bernard J Pope  4   7 , Mark A Jenkins  8 , John L Hopper  8 , Melissa C Southey  9 , Finlay A Macrae  10   11   12 , Ingrid M Winship  10   11 , Aung Ko Win  8   10
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Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1

Daniel D Buchanan et al. Genet Med. 2018 Aug.

Erratum in

Abstract

Background: 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).

Methods: We 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 in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis.

Results: We observed 67 CRCs (mean age at diagnosis = 50.2 (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 up to the age of 70 years (95% confidence interval) for males and females, respectively, to be 28% (95% CI, 10–42%) and 21% (95% CI, 7–33%) for POLE mutation carriers and 90% (95% CI, 33–99%) and 82% (95% CI, 26–99%) for POLD1 mutation carriers.

Conclusion: CRC risks for POLE mutation carriers are sufficiently high to warrant consideration of colonoscopy screening and implementation of management guidelines recommended for MSH6 mutation carriers in cases of Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.

Keywords: POLD1; POLE; colorectal cancer; penetrance; polymerase proofreading–associated polyposis.

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Conflict of interest statement

Conflict of Interest Statement: The authors declare they hold no conflict of interest with respect to this work.

Figures

Figure 1
Figure 1
Cumulative risks (unbroken lines) and corresponding 95% confidence intervals (dotted lines) of colorectal cancer for (A) POLE mutation carriers, (B) POLD1 mutation carriers, and for the general population* (dashed lines). Blue and red represent males and females, respectively. *based on SEER (9 Registries): White (2003–2007) incidence data. SEER, Surveillance, Epidemiology and End Results database.
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