Enrichment of Low Penetrance Susceptibility Loci in a Dutch Familial Colorectal Cancer Cohort

Middeldorp, Anneke; Jagmohan–Changur, Shantie; Eijk, Ronald van; Tops, Carli; Devilee, Peter; Vasen, Hans F. A.; Hes, Frederik J.; Houlston, Richard S.; Tomlinson, Ian; Houwing-Duistermaat, Jeanine J.; Wijnen, Juul T.; Morreau, Hans; Wezel, Tom van

doi:10.1158/1055-9965.epi-09-0601

Cited by 63 publications

(67 citation statements)

References 28 publications

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“…To the best of our knowledge, several studies corroborated the role of rs12953717 polymorphism in cancer susceptibility (Broderick et al, 2007;Tomlinson et al, 2008;Curtin et al, 2009;Middeldorp et al, 2009;Pittman et al, 2009;Slattery et al, 2010;Ho et al, 2011;Li et al, 2011). According to previous cancer-susceptibilitystudies which mainly revealed the remarkable association between the SMAD7 SNP and the risk of CRC, our study demonstrated that allele T at rs12953717 can increase the risk of CRC.…”

Section: Discussionsupporting

confidence: 77%

Intronic Polymorphisms of the SMAD7 Gene in Association with Colorectal Cancer

Damavand

Derakhshani²,

Saeedi³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Based on genome-wide association studies (GWAS) a linkage between several variants such as single nucleotide polymorphisms (SNPs) in intron 3 of SMAD7 (mothers against decapentaplegic homolog7) were, rs12953717, rs4464148 and rs4939827 has been noted for susceptibility to colorectal cancer (CRC). In this study we investigated the relationship of rs12953717 and rs4464148 with risk of CRC among 487 Iranian individuals based on a casecontrol study. Genotyping of SNPs was performed by PCR-RFLP and for confirming the outcomes, 10% of genotyping cases were sequenced with RFLP. Comparing the case and control group, we have found significant association between the rs4464148 SNP and lower risk of CRC. The AG genotype showed decreased risk with and odds ratio of 0.635 (adjusted OR=0.635, 95% CI: 0.417-0.967, p=0.034). There was no significant difference in the distribution of SMAD7 gene rs12953717 TT genotype between two groups of the population evaluated (adjusted OR=1.604, 95% CI: 0.978-2.633, p=0.061). On the other hand, rs12953717 T allele showed a statistically significant association with CRC risk (adjusted OR=1.339, 95% CI: 1.017-1.764, p=0.037). In conclusion, we found a significant association between CRC risk and the rs4464148 AG genotype. Furthermore, the rs12953717 T allele may act as a risk factor. This association may be caused by alternative splicing of pre mRNA. Although we observed a strong association with rs4464148 GG genotype in affected women, we did not detect the same association in CRC male patients.

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Section: Discussionsupporting

confidence: 77%

Intronic Polymorphisms of the SMAD7 Gene in Association with Colorectal Cancer

Damavand

Derakhshani²,

Saeedi³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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“…DNA from index patients with colorectal polyposis 15 and familial CRC 16 was analysed for POLE NM_006231.2:c.1270C4G, p.(Leu424Val) and POLD1 NM_002691.1:c.1433G4A, p.(Ser478Asn). Leucocyte DNA from 485 polyposis cases was included.…”

Section: Materials and Methods Samplesmentioning

confidence: 99%

“…These samples were described before, only DNA that passes quality check was included in the study. 16 The study was approved by the local medical ethical committee of the Leiden University Medical Center (P01-019).…”

Section: Materials and Methods Samplesmentioning

confidence: 99%

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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“…The SNP rs6983267 on chromosome 8q24. 21 was the first to be identified as a common susceptibility variant for CRC by three GWAS in the United Kingdom, Canada, and Scotland (7)(8)(9). The second SNP rs4939827 on 18q21.1 harboring SMAD7, a strong candidate gene, has subsequently been identified by a GWAS in the United Kingdom and further confirmed by another GWAS in Scotland (10,11).…”

Section: Introductionmentioning

confidence: 94%

Risk of Genome-Wide Association Study–Identified Genetic Variants for Colorectal Cancer in a Chinese Population

Xiong

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Recent genome-wide association studies have identified 10 single nucleotide polymorphisms (SNP) associated with colorectal cancer (CRC) in Caucasians. This study evaluated the effects of these newly identified SNPs in a Chinese population.Methods: We assessed the associations of these 10 SNPs with CRC in a case-control study that consisted of 2,124 cases and 2,124 controls. Odds ratios (OR) and 95% confidence intervals were computed by logistic regression, and cumulative effect of risk genotypes were also calculated.Results: We found that only five SNPs (rs6983267, rs4939827, rs10795668, rs3802842, and rs961253) were significantly associated with risk of CRC in our study population in the same direction as reported by previous genome-wide association studies, with the ORs ranging from 1.11 to 2.96. A cumulative effect was observed with the ORs being gradually elevated with increasing number of risk genotypes (P trend = 1.32 × 10 −21 ), and patients carrying ≥4 risk genotypes had 3.25-fold increased CRC risk (95% confidence interval,

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Enrichment of Low Penetrance Susceptibility Loci in a Dutch Familial Colorectal Cancer Cohort

Cited by 63 publications

References 28 publications

Intronic Polymorphisms of the SMAD7 Gene in Association with Colorectal Cancer

Intronic Polymorphisms of the SMAD7 Gene in Association with Colorectal Cancer

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

Risk of Genome-Wide Association Study–Identified Genetic Variants for Colorectal Cancer in a Chinese Population

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