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Prevalence of the variant allele rs61764370 T>G in the 3′UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families

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Abstract

Recently, a variant allele in the 3′UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, we also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. Importantly, results from the current study suggest that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.

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Acknowledgments

We wish to thank all members of the breast cancer families that have participated in this study. We also thank Renée Foekens, Bahar Özturk, Marc Kribbe, and Rahena van Kampen-Binda for assistance with collecting DNA samples. Financial support was provided by the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO), a K08 grant from the NIH [CA124484] and a CTSA Grant, Number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research.

Conflict of interest

Joanne B. Weidhaas has founded a company that has licensed IP discussed in this article.

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Authors and Affiliations

  1. Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Antoinette Hollestelle, Maartje Hooning, Ellen Crepin, Mieke Schutte, Maxime Look, Caroline Seynaeve & John W. M. Martens

  2. Cancer Genomics Centre, Rotterdam, The Netherlands

    Antoinette Hollestelle

  3. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. Margriet Collee, Anja Nieuwlaat & Ans M. W. van den Ouweland

  4. Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    Lambert C. J. Dorssers

  5. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Yurii S. Aulchenko

  6. Department of Genetics, Yale University, New Haven, USA

    Cory Pelletier

  7. Department of Therapeutic Radiology, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA

    Cory Pelletier & Joanne B. Weidhaas

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  1. Antoinette Hollestelle
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Correspondence to Antoinette Hollestelle or Joanne B. Weidhaas.

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Hollestelle, A., Pelletier, C., Hooning, M. et al. Prevalence of the variant allele rs61764370 T>G in the 3′UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families. Breast Cancer Res Treat 128, 79–84 (2011). https://doi.org/10.1007/s10549-010-1080-z

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