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Germline RECQL mutations are associated with breast cancer susceptibility

A Corrigendum to this article was published on 29 March 2016

This article has been updated

Abstract

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.643C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

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Figure 1: Pedigrees for two RECQL mutation carriers.

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NCBI Reference Sequence

Change history

  • 12 January 2016

    In the version of this article initially published, one of the variants was incorrectly reported as c.634C>T. The correct nomenclature for this variant is c.643C>T. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This paper is dedicated to the memory of Parviz Ghadirian. The whole-exome sequencing and part of the Sanger sequencing for these projects were carried out by the McGill University and Génome Québec Innovation Centre. The study was funded in part by the Polish National Science Centre on the basis of decision number DEC-2011/03/N/NZ2/01510 and by the Women's College Research Institute's internal fund. W.D.F. was funded by Susan G. Komen and the Cancer Research Society/Quebec Breast Cancer Foundation. B.R. was funded by Fundación Alfonso Martín Escudero and a fellowship from the Cedars Cancer Institute. J.C.-Z. was funded by the Canadian Institutes of Health Research (CIHR). P.N.T. was funded by the Cancer Research Society, the Quebec Breast Cancer Foundation and the Fonds de Recherche du Québec–Santé. M.R.A. is funded by the Canadian Cancer Society Research Institute and the Canadian Breast Cancer Foundation.

Author information

Authors and Affiliations

Authors

Contributions

C.C. contributed to study design, data collection and interpretation of the Polish study and assisted with the drafting of the manuscript. J.C.-Z., J.N. and J.M. contributed to exome data analysis for the French-Canadian study and assisted with the drafting of the manuscript. W.K., A.K., D.W., A.J., H.R., M.L., B.M. and B.G. contributed to data collection for the Polish study. B.R. and N.H. contributed to sample genotyping for the French-Canadian study and assisted with the drafting of the manuscript. S.G. and S.Z. contributed to sample genotyping for the French-Canadian study. T.H., J.G., T.B., M.S. and T.D. contributed to data collection and provided study subjects for the Polish study. P.N.T. and F.R. contributed to data collection and provided study subjects for the French-Canadian study, and they also assisted with the drafting of the manuscript. J.L. contributed to study design and provided study subjects for the Polish study. W.D.F. contributed to study design and data interpretation, provided study subjects for the French-Canadian study and also assisted with the drafting of the manuscript. S.A.N. contributed to study design and data interpretation for both the Polish and French-Canadian studies, provided study subjects for the French-Canadian study and also assisted with the drafting of the manuscript. M.R.A. contributed to study design, analysis of the exome and Sanger sequencing data, and interpretation of the data for both the Polish and French-Canadian studies and also drafted the manuscript.

Corresponding author

Correspondence to Mohammad R Akbari.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Splicing effect of the RECQL c.1667_1667+3delAGTA mutation.

To investigate the effect of the RECQL c.1667_1667+3delAGTA mutation on the expression of RECQL mRNA, total RNA was extracted from the white blood cells of four mutation carriers and three non-carriers, and cDNA libraries were constructed. A 452-bp sequence from RECQL mRNA was amplified using primers designed to overlap the regions between exons 11 and 12 (forward primer) and exons 14 and 15 (reverse primer). The amplified RECQL mRNA was electrophoresed in a 3% agarose gel. Both carriers of c.1667_1667+3delAGTA mutations (samples 4–7) and non-carriers (samples 1–3) showed the expected 452-bp DNA band, whereas only the mutation carriers (samples 4–7) showed a longer DNA fragment (I, sample 8 is a negative control). Sequencing of PCR products from non-carriers (a) and carriers (b) showed that the extra fragment seen in carriers of c.1667_1667+3delAGTA mutation does not have the deleted single nucleotide (A) at the 3′ end of exon 13; however, it has an insertion of 28 bp from the 5′ end of intron 13 following the three nucleotides (GTA) deleted from this intron, resulting in a net addition of 27 bp to the mRNA spliced from the mutated allele that leads to the loss of a lysine at codon 555 and an insertion of 10 amino acids (MYKLIHYSFR) from codon 555 to 564 of the RECQL protein.

Supplementary Figure 2 Pedigrees of RECQL mutation carriers.

This figure shows the pedigrees of nine RECQL c.1667_1667+3delAGTA mutation carriers who have a positive family history for breast cancer and who were identified from 13,611 women with breast cancer not selected for a family history of cancer. The type of cancer and age at diagnosis are indicated next to the symbol. A plus sign (+) indicates mutation carriers. PSU, primary cancer site unknown.

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Cybulski, C., Carrot-Zhang, J., Kluźniak, W. et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet 47, 643–646 (2015). https://doi.org/10.1038/ng.3284

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