Landscape of mutations in DNA repair genes in young women with breast cancer

There is a geographical difference in the distribution of breast cancer (BC) incidence for young women with BC (YWBC) under 40 years old (y.o.), with 15% in Latin America (LA) versus 7% in high-income countries. Most YWBC are generally diagnosed in advanced stages and with larger tumors. Multiple altered DNA repair genes are implied in BC predisposition, development, and outcome. Among these, pathogenic variants in BRCA1/2 genes account for 50–60%, the remaining to non-BRCA genes like ATM, PALB2, and RAD51. Moreover, germline alterations in DNA repair genes have been reported in YWBC. Considering that cancer cell lines databases analysis can be used to test causal hypotheses and search for new therapeutic agents. We compared BC cell lines and DNA repair variants reported in YWBC from LA. We identified only 6 BC cell lines that carry three variants for TP53 and 2 variants for BRCA1. This shows an underrepresentation for variants in LA in commercial BC cell lines used in preliminary drug studies. Further, to identify rare likely pathogenic variants for DNA repair genes, we analyzed our cohort of 115 Mexican women ≤40 years with BC. Fourty variants were identified in 18 DNA repair genes. 80% of variants were not reported in databases like COSMIC. A frequency of 35.6% of rare, likely pathogenic variants (RLPV) was observed. There are lifestyle factors that might influence the penetrance of DNA repair gene mutations. Herein, associations were found for Luminal BC and smoking for RLPV in DNA repair genes. Considering the roles of these genes in DNA repair it is possible to suggest an additive effect in terms of absolute risk in these mutation carriers. While there are several reports of germline and somatic variants in BC from Latin America (LA), they are scarce compared to other populations. Identifying and studying of RLPV in YWBC will allow more informed decisions concerning BC treatment and prevention.

https://orcid.org/0000-0002-7783-026X