Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifiesFANCMas a susceptibility gene for estrogen-receptor-negative breast cancer

Abstract

ABSTRACTIntroductionBreast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes.MethodsWe conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk.ResultsWe saw a strong association of LoF variants inFANCMwith ER-negative BC (p=4.1×10−7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes,BRCA1(p=2.3×10−10, OR [CI]: 24.9 [6.1-102.5]),BRCA2(p=8.4×10−10, OR [CI]: 7.0 [3.5-14.0]), andPALB2(p=1.8×10−8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations withCHEK2, RAD51D, andTP53.ConclusionIn H/L women, LoF variants inFANCMwere strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate thatFANCMshould be added to BC gene panels.