Mutation and association analysis of GEN1 in breast cancer susceptibility

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

    Research output: Contribution to journalArticlepeer-review


    GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 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 GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. 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. © 2010 Springer Science+Business Media, LLC.
    Original languageEnglish
    Pages (from-to)283-288
    Number of pages5
    JournalBreast Cancer Research and Treatment
    Issue number1
    Publication statusPublished - Nov 2010


    • Breast cancer
    • Cancer genes
    • DNA repair
    • Genetic susceptibility


    Dive into the research topics of 'Mutation and association analysis of GEN1 in breast cancer susceptibility'. Together they form a unique fingerprint.

    Cite this