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Open Access 01-12-2018 | Research article

FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Authors: Tú Nguyen-Dumont, Aleksander Myszka, Pawel Karpinski, Maria M. Sasiadek, Hayane Akopyan, Fleur Hammet, Helen Tsimiklis, Daniel J. Park, Bernard J. Pope, Ryszard Slezak, Nataliya Kitsera, Aleksandra Siekierzynska, Melissa C. Southey

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

Background

FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine.

Methods

We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease.

Results

Among 427 women screened, we identified one carrier of the FANCM:c.1972C > T nonsense mutation (0.23%), and two carriers of the frameshift insertion FANCM:c.1491dup (0.47%). None of the variants we observed in RECQL were predicted to be loss-of-function mutations by standard variant effect prediction tools.

Conclusions

Our study of the Polish and Ukrainian populations has identified a carrier frequency of truncating mutations in FANCM consistent with previous reports. Although initial reports suggesting that mutations in RECQL could be associated with increased breast cancer risk included women from Poland and identified the RECQL:c.1667_1667 + 3delAGTA mutation in 0.23–0.35% of breast cancer cases, we did not observe any carriers in our study cohort. Continued screening, both in research and diagnostic settings, will enable the accumulation of data that is needed to establish the clinical utility of including RECQL and FANCM on gene panel tests.

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Easton DF, Pharoah PD, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, Devilee P, Meindl A, Couch FJ, Southey M, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372(23):2243–57.CrossRefPubMedPubMedCentral

Nguyen-Dumont T, Stewart J, Winship I, Southey MC. Rare genetic variants: making the connection with breast cancer susceptibility. AIMS Genet. 2015;2(4):281–92.CrossRef

BROCA Cancer Risk Panel [http://tests.labmed.washington.edu/BROCA]. Accessed June 2017.

Kiiski JI, Pelttari LM, Khan S, Freysteinsdottir ES, Reynisdottir I, Hart SN, Shimelis H, Vilske S, Kallioniemi A, Schleutker J, et al. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc Natl Acad Sci U S A. 2014;111(42):15172–7.CrossRefPubMedPubMedCentral

Peterlongo P, Catucci I, Colombo M, Caleca L, Mucaki E, Bogliolo M, Marin M, Damiola F, Bernard L, Pensotti V, et al. FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor. Hum Mol Genet. 2015;24(18):5345–55.CrossRefPubMedPubMedCentral

Neidhardt G, Hauke J, Ramser J, Gross E, Gehrig A, Muller CR, Kahlert AK, Hackmann K, Honisch E, Niederacher D et al: Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. JAMA Oncol. 2017;3(9):1245–8.

Sun J, Wang Y, Xia Y, Xu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genet. 2015;11(5):e1005228.CrossRefPubMedPubMedCentral

Cybulski C, Carrot-Zhang J, Kluzniak W, Rivera B, Kashyap A, Wokolorczyk D, Giroux S, Nadaf J, Hamel N, Zhang S, et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet. 2015;47(6):643–6.CrossRefPubMed

Akbari MR, Cybulski C. RECQL: a DNA helicase in breast cancer. Oncotarget. 2015;6(29):26558–9.CrossRefPubMedPubMedCentral

10.

Bogdanova N, Pfeifer K, Schurmann P, Antonenkova N, Siggelkow W, Christiansen H, Hillemanns P, Park-Simon TW, Dork T. Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe. Familial Cancer. 2017;16(2):181–6.CrossRefPubMed

11.

Berliner JL, Fay AM, Practice Issues Subcommittee of the National Society of Genetic Counselors’ Familial Cancer Risk Counseling Special Interest G. Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of genetic Counselors. J Genet Couns. 2007;16(3):241–60.CrossRefPubMed

12.

Nguyen-Dumont T, Hammet F, Mahmoodi M, Tsimiklis H, Teo ZL, Li R, Pope BJ, Terry MB, Buys SS, Daly M. Mutation screening of PALB2 in clinically ascertained families from the breast cancer family registry. Breast Cancer Res Treat. 2015;149(2):547–54.CrossRefPubMedPubMedCentral

13.

Pope BJ, Nguyen-Dumont T, Hammet F, Park DJ. ROVER variant caller: read-pair overlap considerate variant-calling software applied to PCR-based massively parallel sequencing datasets. Source Code Biol Med. 2014;9(1):3.CrossRefPubMedPubMedCentral

14.

Münz M, Ruark E, Renwick A, Ramsay E, Clarke M, Mahamdallie S, Cloke V, Seal S, Strydom A, Lunter G et al: CSN and CAVA: variant annotation tools for rapid, robust next-generation sequencing analysis in the clinic. Genome Med. 2015;7:76.

15.

Adzhubei I, Jordan DM, Sunyaev SR: Predicting functional effect of human missense mutations using PolyPhen-2. Current protocols in human genetics / editorial board, Jonathan L Haines [et al] 2013, Chapter 7:Unit7 20.

16.

Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.CrossRefPubMedPubMedCentral

17.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.CrossRefPubMedPubMedCentral

Title: FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine
Authors: Tú Nguyen-Dumont
Aleksander Myszka
Pawel Karpinski
Maria M. Sasiadek
Hayane Akopyan
Fleur Hammet
Helen Tsimiklis
Daniel J. Park
Bernard J. Pope
Ryszard Slezak
Nataliya Kitsera
Aleksandra Siekierzynska
Melissa C. Southey
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0524-x

At a glance: The STEP trials

Springer Medicine

FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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