FANCM and RECQL genetic variants and breast cancer susceptibility

Relevance to South Poland and West Ukraine

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

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number12
Number of pages7
JournalBMC Medical Genetics
Volume19
Issue number1
DOIs
Publication statusPublished - 19 Jan 2018
Externally publishedYes

Keywords

  • Breast cancer predisposition
  • Familial breast cancer
  • FANCM
  • Gene panel testing
  • RECQL

Cite this

Nguyen-Dumont, Tú ; Myszka, Aleksander ; Karpinski, Pawel ; Sasiadek, Maria M. ; Akopyan, Hayane ; Hammet, Fleur ; Tsimiklis, Helen ; Park, Daniel J. ; Pope, Bernard J. ; Slezak, Ryszard ; Kitsera, Nataliya ; Siekierzynska, Aleksandra ; Southey, Melissa C. / FANCM and RECQL genetic variants and breast cancer susceptibility : Relevance to South Poland and West Ukraine. In: BMC Medical Genetics. 2018 ; Vol. 19, No. 1.
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title = "FANCM and RECQL genetic variants and breast cancer susceptibility: Relevance to South Poland and West Ukraine",
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.",
keywords = "Breast cancer predisposition, Familial breast cancer, FANCM, Gene panel testing, RECQL",
author = "T{\'u} Nguyen-Dumont and Aleksander Myszka and Pawel Karpinski and Sasiadek, {Maria M.} and Hayane Akopyan and Fleur Hammet and Helen Tsimiklis and Park, {Daniel J.} and Pope, {Bernard J.} and Ryszard Slezak and Nataliya Kitsera and Aleksandra Siekierzynska and Southey, {Melissa C.}",
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Nguyen-Dumont, T, Myszka, A, Karpinski, P, Sasiadek, MM, Akopyan, H, Hammet, F, Tsimiklis, H, Park, DJ, Pope, BJ, Slezak, R, Kitsera, N, Siekierzynska, A & Southey, MC 2018, 'FANCM and RECQL genetic variants and breast cancer susceptibility: Relevance to South Poland and West Ukraine', BMC Medical Genetics, vol. 19, no. 1, 12. https://doi.org/10.1186/s12881-018-0524-x

FANCM and RECQL genetic variants and breast cancer susceptibility : Relevance to South Poland and West Ukraine. / Nguyen-Dumont, Tú; Myszka, Aleksander; Karpinski, Pawel; Sasiadek, Maria M.; Akopyan, Hayane; Hammet, Fleur; Tsimiklis, Helen; Park, Daniel J.; Pope, Bernard J.; Slezak, Ryszard; Kitsera, Nataliya; Siekierzynska, Aleksandra; Southey, Melissa C.

In: BMC Medical Genetics, Vol. 19, No. 1, 12, 19.01.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - FANCM and RECQL genetic variants and breast cancer susceptibility

T2 - Relevance to South Poland and West Ukraine

AU - Nguyen-Dumont, Tú

AU - Myszka, Aleksander

AU - Karpinski, Pawel

AU - Sasiadek, Maria M.

AU - Akopyan, Hayane

AU - Hammet, Fleur

AU - Tsimiklis, Helen

AU - Park, Daniel J.

AU - Pope, Bernard J.

AU - Slezak, Ryszard

AU - Kitsera, Nataliya

AU - Siekierzynska, Aleksandra

AU - Southey, Melissa C.

PY - 2018/1/19

Y1 - 2018/1/19

N2 - 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.

AB - 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.

KW - Breast cancer predisposition

KW - Familial breast cancer

KW - FANCM

KW - Gene panel testing

KW - RECQL

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U2 - 10.1186/s12881-018-0524-x

DO - 10.1186/s12881-018-0524-x

M3 - Article

VL - 19

JO - BMC Medical Genetics

JF - BMC Medical Genetics

SN - 1471-2350

IS - 1

M1 - 12

ER -