Defects in DNA damage recognition and repair has been implicated in hereditary breast cancer (BC). Several studies demonstrated, that Fanconi Anemia (FA) associated genes-coding proteins and products of BRCA1/2 genes cooperate in a DNA repair pathway which is required for resistance to DNA interstrand crosslinks. Our aim was to analyze nucleotide variants in FA genes predisposing with an increased risk of hereditary cancers.
Targeted NGS was performed in a cohort of 630 BC patients with strong evidence of hereditary background of cancer. The NimbleGenSeqCap EZ Choice® kit (Roche) was used for target enrichment, and sequencing was performed using Illumina MiSeq® (Illumina) following manufacturers protocol.
Mutations Mean age (range) HER 2+, % HER2-, % Triple negative BC Logistic likelihood ratio, test P FA genes 52 (25-69) 33.7 66,3 25,0 0,011 BRCA1/2 42 (25-67) 20,9 71,9 47,5 0,002 All hereditary breast cancer 61 (22-88) 58,7 41,3 17,9 0,452
36 (5,7%) patients had heterozygous mutations in PALB2, FANCI, FANCL, FANCC, FAM175A, FANCM, FANCG, FANCD2 genes implicated in the causation of FA. Among these variants 30,5% were pathogenic, and 69,5% had uncertain significance. All variants had strong susceptibility with BC, the combined odds ratio of having a mutation was 27,3 (95% CI 1,25–4,64;P = 0,002)Six patients carried complementary pathogenic mutations in BRCA1/2, XRCC2 or MLH3 genes. Heterozygous mutations PALB2 and FANCL were significantly associated with estrogen receptor (ER)-positive disease, while those in FANCI were associated with ER-negative BC. Mutations in FANCI and FANCL genes had an association with progesterone receptor (PR)-negative BC, and PALB2 mutations were associated with PR-positive BC.
Heterozygous germline mutations in FA genes are strongly associated with a higher risk of BC. Triple negative BC is more common among carriers of mutations in FA genes than in common cohort of BC patients. Clinical characteristics of women with different germline mutations inBC.
The reported study was funded by Russian Foundation for Basic Research grant no 18-415-160009 and by the Russian Government Program of Competitive Growth of Kazan Federal University
National BioService, Saint Petersburg, Russian Federation.
Kazan Federal University.
All authors have declared no conflicts of interest.