Breast cancer susceptibility: current knowledge and implications for genetic counselling

Abstract

Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

Hereditary breast and ovarian cancer susceptibility genes (Review)

“…Genome-wide association studies identified other genetic factors that increase the risk of breast and ovarian cancers. In addition to BRCA1 and BRCA2 mutations, putative susceptibility genes for hereditary breast and ovarian cancer include BRCA1/2 function modifier genes and DNA repair modifier genes with high penetrance (CDH1, NBS1, NF1, PTEN, TP53 and STK11), moderate penetrance (ATM, ATR, BRIP1,CHEK2, PALB2, CDK1 and RAD50), and low penetrance (FGFR2, LSP1, MAP3K1, TGFB1, TOX3, VEGF, PGR, KRAS and PARP) (3,68). Although some of the factors were validated, various studies suggest the existence of disease susceptibility differences within ethnic populations.…”

Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility

“…Diverse FGF10, FGFR2 and MAP3K1 gene polymorphisms have already been identified as breast cancer susceptible in various populations (Rebbeck et al 2009;Ripperger 2009;Harlid et al 2012;Jara et al 2013;Murillo-Zamora et al 2013;Pritchard and Hayward 2013;Siddiqui et al 2014;Zheng et al 2014;Campbell et al 2016), and studies on breast cancer genetic background have also been performed in Slovakia (Franeková et al 2007;Zubor et al 2007Zubor et al , 2008Zubor et al , 2014Kasajová et al 2016). Results from these studies emphasised the relevance of several polymorphisms in breast cancer susceptibility and pointed out the importance of an inter-population genetic variability.…”

Can a phenotype for recessive inheritance in breast cancer be defined?

“…BRCA1, BRCA2 and other known susceptibility genes account for approximately 20% of this effect (3), the high-susceptibility genes (such as PTEN, STK11, TP53) together with moderate-susceptibility (such as CHK2, ATM, PALB2, BRIP1) account for around 2%, whereas approximately 4% is credited to the low-susceptibility genes (such as FGFR2, TOX3, MAP3K1, LSP1) (4,5), this leaves approximately 75 % of all familial breast cancer unexplained.…”