Mutation and association analysis of in breast cancer susceptibility

Clare Turnbull (1) , Sarah Hines (1) , Anthony Renwick (1) , Deborah Hughes (1) , David Pernet (1) , Anna Elliott (1) , Sheila Seal (1) , Margaret Warren-Perry (1) , D. Gareth Evans (2) , Diana Eccles (3) , Michael R. Stratton (1, 4) , Nazneen Rahman (1)

1 Section of Cancer Genetics
2 Regional Genetic Service
3 Wessex Clinical Genetics Service
4 Cancer Genome Project

GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating mutations have been reported in two breast cancers. Together these data led to the proposition that is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of in 176 /-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common variants. These data indicate that although it also plays a key role in double-strand DNA break repair, does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like , , , , and and that common variants do not act as low-penetrance susceptibility alleles analogous to SNPs in . Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case–control association analyses, to evaluate the contribution of genes to cancer susceptibility.

Mots clés: Breast cancer; Genetic susceptibility; DNA repair; Cancer genes

Clare Turnbull, Sarah Hines, Anthony Renwick, Deborah Hughes, David Pernet, et al.. Mutation and association analysis of in breast cancer susceptibility. Breast Cancer Research and Treatment, 2010, 124 (1), pp.283-288. ⟨10.1007/s10549-010-0949-1⟩. ⟨hal-00541154⟩