2012
DOI: 10.1038/ng.2503
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Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

Abstract: Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposi… Show more

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Cited by 876 publications
(911 citation statements)
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“…Further analysis of the CRCs with POLE exonuclease domain mutations (EDM) in the TCGA data demonstrated an increase in all types of base substitutions. C:G>T:A was the most common mutation type, but compared to other cancers the relative increase in G:C>T:A was most dramatic [2]. …”
Section: Molecular Tumor Boardmentioning
confidence: 99%
“…Further analysis of the CRCs with POLE exonuclease domain mutations (EDM) in the TCGA data demonstrated an increase in all types of base substitutions. C:G>T:A was the most common mutation type, but compared to other cancers the relative increase in G:C>T:A was most dramatic [2]. …”
Section: Molecular Tumor Boardmentioning
confidence: 99%
“…Germline variants in the genes LKB1 , SMAD4 , GREM1 , PTEN , BMPR1A and AXIN2 have also been implicated in predisposition to colorectal cancer and highlight a role for many pathways in tumourigenesis of the colon 5. More recently, germline variants in the exonuclease domains of the polymerase‐ϵ catalytic subunit gene ( POLE ) and in the DNA polymerase delta catalytic subunit ( POLD1 ) gene have been linked to colorectal adenoma and carcinoma development 6. Variants in POLE and POLD1 dramatically increase the somatic mutation rate, resulting in C:G → T:A somatic base changes 7.…”
Section: Introductionmentioning
confidence: 99%
“…Mutations in the DNA polymerase ɛ gene ( POLE ) were recently reported as predisposing for inherited colorectal cancer (Palles et al, 2013). In a previous study we present a mutation in the proof‐reading exonuclease domain of this protein in a large Swedish family with CRC (Rohlin et al, 2014), Supporting Information Table S1.…”
Section: Resultsmentioning
confidence: 99%
“…The reason for this additional sequencing was that heterozygote mutations in the DNA polymerase genes, POLD1 and POLE , were recently identified in patients with multiple adenoma and/or CRC. The mutations were restricted to the proofreading exonuclease domain of the proteins (Palles et al, 2013). We have recently reported a family with a mutation in the exonuclease domain of POLE in Sweden.…”
Section: Discussionmentioning
confidence: 99%
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