New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis

Valle, Laura; Hernández‐Illán, Eva; Bellido, Fernando; Aiza, Gemma; Castillejo, Adela; Navarro, Matilde; Seguí, Núria; Vargas, Gardenia; Guarinós, Carla; Juárez, Míriam; Sanjuán, Xavier; Iglesias, Sílvia; Alenda, Cristina; Egoavil, Cecilia; Segura, Ángel; Juan, María José; Rodríguez–Soler, María; Brunet, Joan; González, Sara; Jover, Rodrigo; Lázaro, Conxi; Capellà, Gabriel; Pineda, Marta; Soto, José Luís; Blanco, Ignacio

doi:10.1093/hmg/ddu058

Cited by 134 publications

(145 citation statements)

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“…In a recent study, the same POLE variant was also detected as a de-novo occurrence in a patient with early onset CRC and polyposis. 14 Interestingly, the germline POLE variant in the currently studied families (PT1, PT2 and PT3) is associated with a Lynch syndrome phenotype with MSI tumours and MSH6 or MSH2/MSH6 protein loss. This contrasts with previously identified POLE and POLD1 germline variant carriers who developed microsatellite stable tumours.…”

Section: Resultsmentioning

confidence: 89%

“…Despite an enrichment in our cohort for inherited CRC and polyposis, the frequency (3 in 1188; 0.25%) is also comparable to the currently reported frequency. 13,14 The first patient (PT1) was diagnosed with a MSI caecum tumour and two adenomas at age 40. She developed, cumulatively, around 30 polyps and presented with a microsatellite stable endometrial cancer at age 50.…”

Section: Resultsmentioning

confidence: 99%

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Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

et al. 2014

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Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C4G, p.(Leu424Val) and POLD1 c.1433G4A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant. INTRODUCTIONFaithful DNA replication and the repair of errors are both essential for the maintenance of genomic stability and suppression of carcinogenesis. 1 Duplication of genomes with high accuracy is achieved through three mechanisms: the high selectivity of DNA polymerases; exonucleolytic proofreading; and post replication mismatch repair. 2 The DNA polymerases ε (POLε) and δ (POLδ) are required for the efficient genome replication in the eukaryotic replication fork. 3 Their major component proteins, encoded by POLE and POLD1, respectively, possess an intrinsic 3′-5′ proofreading domain that removes incorrectly inserted nucleotides during DNA synthesis. [4][5][6][7][8][9] Studies in the yeast have shown that mutations in the proofreading domains of POLε or POLδ increase spontaneous mutation rates. 8,9 In addition, somatic mutations in the proofreading domains of POLD1 and POLE have been identified in microsatellite instable (MSI) and hypermutated subgroups of colorectal cancers (CRCs). [10][11][12] Recently, Palles et al reported that heterozygous germline variants in the proofreading domain of the DNA polymerases POLE and POLD1 predispose, with a high penetrance, to multiple colorectal adenomas, early onset CRC (OMIM #114500) and endometrial cancer (OMIM #608089). These variants were found by whole-genome sequencing and linkage analysis in three large families with a dominant pattern of CRC and multiple adenomas. 13 Subsequent screening of 3805 CRC patients revealed that these variants are relatively rare: POLE

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

et al. 2014

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“…Approximately 3% of colorectal and 7% of endometrial cancers are reported with mutations in the proofreading domain of POLE (POLE-exo*) (The Cancer Genome Atlas Network 2012; Church et al 2013;Palles et al 2013;Kane and Shcherbakova 2014;Meng et al 2014;Valle et al 2014;Zou et al 2014). The mutation incidence in tumors with this defect often exceeds 100 mutations/Mb.…”

mentioning

confidence: 99%

“…Although some colorectal and endometrial tumors have been reported with POLD1 exonuclease mutations (POLD1-exo*) Valle et al 2014), their relationship to the mutational properties of those tumors is not clear. Preliminary data on survival of patients harboring mutations in POLE suggest they have significantly better outcomes (The Cancer Genome Atlas Network 2013; Meng et al 2014) and therefore may require less aggressive treatment.…”

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confidence: 99%

Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication

et al. 2014

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Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT!TAT and TCG!TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C!A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.

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“…To this end, the term "polymerase proofreading-associated polyposis" (PPAP) has been suggested [52]. POLE and POLD1 mutations may be inherited or arise de novo [53]. Germline mutations in these two genes appear to be fairly rare, and relatively few syndromic patients have been identified to date.…”

Section: Pole/pold1-associated Syndromementioning

confidence: 99%

Current applications of molecular pathology in colorectal carcinoma

2017

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Molecular pathology is playing an increasingly important role in the treatment and overall management of patients with colorectal carcinoma. Three distinct genetic pathways have been identified that play a role in carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the CpG island methylator phenotype pathway. Certain genetic mutations, some of which overlap with the aforementioned pathways, can also indicate that a carcinoma patient has a genetic predisposition syndrome, such as familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes. A variety of advanced methods, including next-generation sequencing, are available to test for these and other mutations, such as targetable mutations that may allow tailoring of a treatment regimen to a patient's specific cancer (e.g., KRAS and BRAF mutations). The possible future role of testing circulating tumor cells is also addressed. New mutations and syndromes continue to be discovered, ensuring that our knowledge of colorectal carcinoma and our ability to treat it will advance in the future.

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New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis

Cited by 134 publications

References 22 publications

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication

Current applications of molecular pathology in colorectal carcinoma

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