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Reply to ‘Mutations in RECQL are not associated with breast cancer risk in an Australian population’

Nature Genetics volume 50, pages 1348–1349 (2018)Cite this article

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Ahmed et al. reply — RECQL was first proposed to be a candidate breast cancer–susceptibility gene in 2015 by our group1 and by a Chinese group2 independently. RECQL helps to overcome stalled DNA replication forks and thereby prevents double-strand DNA breaks. Cells with defective RECQL accumulate more double-strand DNA breaks than normal cells. In our initial analysis of French–Canadian and Polish patients with breast cancer1, we identified two rare but recurrent RECQL mutations (one in each population); each was significantly more frequent among patients with breast cancer than among controls in the respective population. In Quebec, 7 of 1,013 patients with high-risk breast cancer carried the c.643C>T (p.Arg215*) variant (NM_002907.3), compared with 1 of 7,136 newborns in Quebec (odds ratio (OR) = 49.3, P <10−5, two-tailed Fisher’s exact test). In Poland, 30 of 13,136 unselected breast cancer cases carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant, compared with 2 of 4,702 controls in Poland (OR = 5.4, P = 0.008, two-tailed Fisher’s exact test). In an independent study from China, Sun et al.2 found nine potentially pathogenic mutations (three nonsense mutations, one splicing mutation, and five deleterious missense mutations) among 448 patients with BRCA-negative familial breast cancer, compared with 1 of 1,588 controls (OR = 31.9, P <10−5, two-tailed Fisher’s exact test). Elsewhere, Kwong et al.3 studied 1,110 Chinese patients from Hong Kong who had high-risk BRCA1- and BRCA2-negative breast cancer, and they found six patients with potentially pathogenic RECQL mutations (one frameshift deletion, two splicing-site mutations, and one nonsense mutation; two mutations were seen in more than one patient). More recently, the original Chinese team that reported RECQL independently from our team screened 62 known cancer-susceptibility genes among 8,085 unselected Chinese patients with breast cancer4. The most commonly mutated genes among their patients were BRCA2, BRCA1, PALB2, and TP53, with 285, 146, 56, and 38 mutation carriers, respectively; RECQL was next, with 30 carriers of 15 different pathogenic mutations (six nonsense mutations, three frameshift insertions, one splicing mutation, and five deleterious missense mutations). Although no new controls were screened, and the same control set as in their initial report2 was used, the risk of breast cancer among RECQL mutation carriers was 5.8-fold higher than among noncarriers. This result is comparable to our initially reported findings1 for unselected Polish patients with breast cancer with a RECQL mutation (OR = 5.4). More recently, Tervasmaki et al.5 have reported a founder RECQL missense mutation (p.Ile156Met) among 6 of 1,946 Finnish patients with breast cancer, whereas none of the 1,539 controls carried that mutation. The presence of rare truncating and missense variants in these five studies from five populations of different ancestry, coupled with the extreme rarity of mutations found in controls, suggested that RECQL was indeed a breast cancer–susceptibility gene.

However, two follow-up studies have presented conflicting evidence. Bogdanova et al.6 have examined the frequency of the recurrent Polish RECQL mutation (c.1667_1667+3delAGTA) in unselected Belarusian and German patients with breast cancer, and observed the mutation in 9 of 2,596 cases (0.35%) and in 6 of 2,132 (0.28%) controls. Whereas the mutation frequency among the cases was similar to that found in the Polish study (0.35% versus 0.23% in Poland), the mutation frequency among the controls in the study by Bogdanova et al. is much higher than that in the Polish controls (0.28% versus 0.04% in Poland). The frequency of this particular mutation in the mixed non-Finnish European population, as reported by The Genome Aggregation Database (gnomAD)7, is 0.09% (70/75,519), a value closer to the mutation frequency in Polish controls (0.04%). However, the gnomAD browser reports mutation frequencies from a mixed European population, and it cannot be formally used to evaluate the pathogenicity of the variant.

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References

  1. Cybulski, C. et al. Nat. Genet. 47, 643–646 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Sun, J. et al. PLoS Genet. 11, e1005228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kwong, A. et al. Breast Cancer Res. Treat. 157, 211–215 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Sun, J. et al. Clin. Cancer Res. 23, 6113–6119 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Tervasmäki, A. et al. Int. J. Cancer 142, 2286–2292 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Bogdanova, N. et al. Fam. Cancer 16, 181–186 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Lek, M. et al. Nature 536, 285–291 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, N. et al. Nat. Genet. https://doi.org/10.1038/s41588-018-0206-9 (2018).

  9. Wacholder, S., Chanock, S., Garcia-Closas, M., El Ghormli, L. & Rothman, N. J. Natl. Cancer Inst. 96, 434–442 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Muzzolini, L. et al. PLoS Biol. 5, e20 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Women’s College Research Institute, Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada

    Humayun Ahmed, Kelly Metcalfe, Steven A. Narod & Mohammad R. Akbari

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Humayun Ahmed, Steven A. Narod & Mohammad R. Akbari

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Jordan Lerner-Ellis

  4. Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada

    Jordan Lerner-Ellis

  5. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

    Cezary Cybulski & Jan Lubiński

  6. Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland

    Cezary Cybulski

  7. Lawrence Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada

    Kelly Metcalfe

  8. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Steven A. Narod & Mohammad R. Akbari

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  1. Humayun Ahmed
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Contributions

All authors are part of the team working on validating the role of RECQL in breast cancer, and they all contributed to writing this correspondence.

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Correspondence to Mohammad R. Akbari.

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Ahmed, H., Lerner-Ellis, J., Cybulski, C. et al. Reply to ‘Mutations in RECQL are not associated with breast cancer risk in an Australian population’. Nat Genet 50, 1348–1349 (2018). https://doi.org/10.1038/s41588-018-0233-6

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