Cargando…

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

INTRODUCTION: Breast 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 H...

Descripción completa

Detalles Bibliográficos
Autores principales: Nierenberg, Jovia L., Adamson, Aaron W., Hu, Donglei, Huntsman, Scott, Patrick, Carmina, Li, Min, Steele, Linda, Tong, Barry, Shieh, Yiwey, Fejerman, Laura, Gruber, Stephen B., Haiman, Christopher A., John, Esther M., Kushi, Lawrence H., Torres-Mejía, Gabriela, Ricker, Charité, Weitzel, Jeffrey N., Ziv, Elad, Neuhausen, Susan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901069/
https://www.ncbi.nlm.nih.gov/pubmed/36747679
http://dx.doi.org/10.1101/2023.01.25.23284924
Descripción
Sumario:INTRODUCTION: Breast 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. METHODS: We 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. RESULTS: We saw a strong association of LoF variants in FANCM with 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]), and PALB2 (p=1.8×10(−8), OR [CI]: 6.5 [3.2–13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53. CONCLUSION: In H/L women, LoF variants in FANCM were 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 that FANCM should be added to BC gene panels.