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Mutations in RECQL are not associated with breast cancer risk in an Australian population

Nature Genetics volume 50, pages 1346–1348 (2018)Cite this article

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To the Editor — The slow progress of intensive international efforts over the past two decades to identify the remaining genetic causes of familial breast cancer suggests that numerous predisposition genes exist, which are likely to be much rarer than BRCA1 and BRCA2, and to each account for a small proportion of families. Searching for very rare risk alleles in the context of population diversity further increases the challenges of identifying and validating new breast cancer–associated genes, as evidenced by the inability of subsequent studies to validate primary reports of new genes1,2,3. Here we argue that the previously reported breast cancer–susceptibility gene RECQL is not associated with breast cancer risk in an Australian population.

Two loss-of-function (LoF) founder mutations in RECQL have been genotyped in Polish and French-Canadian subjects, and a greater-than-fivefold-increased risk has been reported for c.1667_1667+3delAGTA carriers in the Polish women (0.23% in 13,136 unselected breast cancer cases versus 0.04% in 4,702 controls)4,5. Likewise, a 16-fold-increased risk has been reported for c.634C>T carriers in French-Canadian subjects with early-onset breast cancer compared with population newborn controls (0.69% in 1,013 cases versus 0.014% in 7,136 controls). At that time, a smaller study of familial breast cancer cases and controls from Han Chinese individuals from Northern China (448 cases and 1,588 controls) supported a role for RECQL in breast cancer predisposition but was underpowered compared with the study reported in Polish and French-Canadian populations6. Another study has reported a 0.54% carrier frequency of RECQL LoF variants in 1,110 high-risk females from Hong Kong with breast cancer; however, very few controls were sequenced (88 controls)7. In contrast, a null result has been reported for the c.1667_1667+3delAGTA variant (reported to be enriched more than fivefold in Polish individuals with breast cancer) among 2,596 breast cancer cases and 2,132 controls (0.35% versus 0.28%, odds ratio 1.23, P = 0.69) from Central European individuals who were likely to have ancestry similar to that of the Polish population8. Because some groups are now suggesting that RECQL be included in germline breast cancer–predisposition testing panels, it is crucial to be certain that this gene has genuine relevance to breast cancer predisposition, because adverse outcomes could potentially arise if the conclusions of the original publications are incorrect or overestimated.

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Acknowledgements

We thank H. Saunders and R. Huynh for processing DNA samples; M. Doyle for helping with bioinformatics analysis; and the Exome Aggregation Consortium and the groups that provided exome variant data for comparison (http://exac.broadinstitute.org/about). The study was funded by the National Breast Cancer Foundation (IF-15-004, I.G.C. and P.A.J.), Cancer Australia (PdCCRS_1107870, I.G.C. and P.A.J.), the Victorian Cancer Agency (Tumor Stream Grant, P.A.J.) and the National Health and Medical Research Council of Australia (GNT1023698, P.A.J.; GNT1041975, I.G.C.).

Author information

Author notes

  1. A full list of members and affiliations appears at http://www.lifepool.org/.

  2. These authors jointly directed this work: Paul A. James, Ian G. Campbell.

Authors and Affiliations

  1. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Na Li, Simone M. Rowley, Lisa Devereux, Jue Er Amanda Lee, Siobhan Hughes, Ella R. Thompson, Alison H. Trainer, Kylie L. Gorringe, Paul A. James & Ian G. Campbell

  2. Cancer Biology Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Na Li

  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Na Li, David L. Goode, Kaushalya C. Amarasinghe, Ella R. Thompson, Jason Li, Kylie L. Gorringe, Paul A. James & Ian G. Campbell

  4. Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    David L. Goode

  5. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Kaushalya C. Amarasinghe, Richard Lupat, Magnus Zethoven & Jason Li

  6. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Simone McInerny, Alison H. Trainer & Paul A. James

  7. LifePool, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Lisa Devereux

  8. Discipline of Medical Genetics, University of Newcastle, Newcastle, New South Wales, Australia

    Michelle W. Wong-Brown & Rodney J. Scott

  9. Centre for Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia

    Michelle W. Wong-Brown & Rodney J. Scott

  10. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Ella R. Thompson

  11. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia

    Alison H. Trainer, Kylie L. Gorringe, Paul A. James & Ian G. Campbell

  12. Division of Molecular Medicine, Pathology North, NSW Health Pathology, Newcastle, New South Wales, Australia

    Rodney J. Scott

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  1. Na Li
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Consortia

LifePool Investigators

Contributions

N.L. contributed to study design, generating sequencing libraries, data analysis and manuscript writing. S.M.R. contributed to generating sequencing libraries, sample management and Sanger sequencing. D.G. contributed to principal-component analysis and plotting. K.C.A., R.L., M.Z. and J.L. contributed to alignment of sequencing reads and variant calling. S.M., L.D. and M.W.W.-B. contributed to collection of study materials or patients. LifePool Investigators, E.R.T. and A.H.T. contributed to data interpretation. J.E.A.L. and S.H. contributed to generating sequencing libraries and quality control. K.L.G. contributed to data interpretation and manuscript revision. R.J.S. contributed to provision of patients’ material and data interpretation. P.A.J. contributed to study design, clinical interpretation and manuscript revision. I.G.C. contributed to study design, data analysis and manuscript revision. All authors contributed to drafting, revising and final approval of the manuscript.

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Correspondence to Ian G. Campbell.

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The authors declare no competing interests.

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Li, N., Rowley, S.M., Goode, D.L. et al. Mutations in RECQL are not associated with breast cancer risk in an Australian population. Nat Genet 50, 1346–1348 (2018). https://doi.org/10.1038/s41588-018-0206-9

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