Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.
Highlights
Breast cancer (BC, OMIM#114480) is the most prevalent cancer in the world and accounts for14.7 million of mortality cases [1]
Mutational status was defined as the presence of a pathogenic or likely pathogenic variant (American College of Medical Genetics and Genomics classification) in any of the 143 genes evaluated [29]
We found that almost one out of three patients (5/17) with BRCA1 pathogenic variants had the Mexican founder mutation, which highlights the additional value of evaluating this alteration through a rapid test, such as the one we used
Summary
Breast cancer (BC, OMIM#114480) is the most prevalent cancer in the world and accounts for14.7 million of mortality cases [1]. Locus heterogeneity has been found in patients without mutations in BRCA1 and BRCA2 [6] together with additional pathogenic variants at lower frequency and in genes that confer moderate risk including CHEK2, PALB2, ATM, FANCM, ATR, STK11, RAD51C, BRIP1, CDH1, NF1, NBN and ERCC3 [7,8]. The prevalence of these novel, moderate-risk genes in HBOC patients has recently started to be defined by massive parallel sequencing (MPS). Studies indicate that causal variants have very low frequency in most of the populations studied and are spread in a larger array of genes that remain unexplored (Table 1)
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