University of Oulu

Tervasmäki, A., Mantere, T., Hartikainen, J., Kauppila, S., Lee, H., Koivuluoma, S., Grip, M., Karihtala, P., Jukkola-Vuorinen, A., Mannermaa, A., Winqvist, R., Pylkäs, K. (2018) Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer. International Journal of Cancer, 142 (11), 2286-2292. doi:10.1002/ijc.31259

Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer

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Author: Tervasmäki, Anna1; Mantere, Tuomo1; Hartikainen, Jaana M.2,3;
Organizations: 1Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre Nordlab Oulu, University of Oulu, Oulu, Finland
2School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
3Department of Clinical Pathology, Imaging Center, Kuopio University Hospital, Kuopio, Finland
4Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
5Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
6Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland
7Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201902215902
Language: English
Published: John Wiley & Sons, 2018
Publish Date: 2019-02-21
Description:

Abstract

Several known breast cancer susceptibility genes with moderate‐to‐high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein‐truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty‐five variants were studied here for the disease association using Finnish breast cancer case (n = 492–2,035) and control (n = 277–1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2–3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles.

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Series: International journal of cancer
ISSN: 0020-7136
ISSN-E: 1097-0215
ISSN-L: 0020-7136
Volume: 142
Issue: 11
Pages: 2286 - 2292
DOI: 10.1002/humu.23411
OADOI: https://oadoi.org/10.1002/humu.23411
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3122 Cancers
Subjects:
Funding: Grant sponsor: The Academy of Finland; Grant numbers: 307808, 314183; Grant sponsor: Center of Excellence; Grant number: 284605; Grant sponsor: The Cancer Foundation of Finland; Grant sponsor: The Sigrid Juselius Foundation; Grant sponsor: The University of Oulu; Grant sponsor: The special Governmental EVO; Grant sponsor: K. Albin Johansson’s Foundation; Grant sponsor: University of Eastern Finland
Academy of Finland Grant Number: 307808
314183
284605
Detailed Information: 307808 (Academy of Finland Funding decision)
314183 (Academy of Finland Funding decision)
284605 (Academy of Finland Funding decision)
Copyright information: This is the peer reviewed version of the following article: Tervasmäki, A., Mantere, T., Hartikainen, J., Kauppila, S., Lee, H., Koivuluoma, S., Grip, M., Karihtala, P., Jukkola-Vuorinen, A., Mannermaa, A., Winqvist, R., Pylkäs, K. (2018) Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer. International Journal of Cancer, 142 (11), 2286-2292. doi:10.1002/ijc.31259, which has been published in final form at https://doi.org/10.1002/ijc.31259. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.