Germline Variants in Cancer Genes from Young Breast Cancer Mexican Patients

SIMPLE SUMMARY: Young, Mexican women are more susceptible to breast cancer compared to other populations. However, studies on germline young, Mexican women are scarce and limited to a panel of 143 genes. This is partially due to the lack of gene annotation tools and difficulties in determining the causal genes in understudied populations. Here, we used whole exome sequencing combined with a powerful annotation tool to analyze 862 cancer genes in 115 young, Mexican women diagnosed with breast cancer. Our results showed well-known genes and many barely reported variants in our population. Moreover, we were able to assign candidate causal genes to 34% of patients, surpassing previous studies. These results suggest that deeper bioinformatic analyses could inform medical decisions to improve diagnosis, treatment, and life expectancy in young women with breast cancer. ABSTRACT: Breast cancer (BC) is one of the most frequent cancer types in women worldwide. About 7% is diagnosed in young women (YBC) less than 40 years old. In Mexico, however, YBC reaches 15% suggesting a higher genetic susceptibility. There have been some reports of germline variants in YBC across the world. However, there is only one report from a Mexican population, which is not restricted by age and limited to a panel of 143 genes resulting in 15% of patients carrying putatively pathogenic variants. Nevertheless, expanding the analysis to whole exome involves using more complex tools to determine which genes and variants could be pathogenic. We used germline whole exome sequencing combined with the PeCanPie tool to analyze exome variants in 115 YBC patients. Our results showed that we were able to identify 49 high likely pathogenic variants involving 40 genes on 34% of patients. We noted many genes already reported in BC and YBC worldwide, such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and POLQ, but also others not commonly reported in YBC in Latin America, such as CLTCL1, DDX3X, ERCC6, FANCE, and NFKBIE. We show further supporting and controversial evidence for some of these genes. We conclude that exome sequencing combined with robust annotation tools and further analysis, can identify more genes and more patients affected by germline mutations in cancer.