Thus, Sig 3 levels can be used to identify new HR genes and new pathogenic variants in genes that lead to BRCA-like tumors. This approach had 100% sensitivity and 98.5 % specificity in classifying 142 known benign and pathogenic missense mutations in BRCA1/2. A variant was classified as a pathogenic or disease-causing variant if the tumor that harbored it showed a second hit and Sig 3. Moreover, we developed a framework to reclassify germline BRCA1/2 variants of unknown significance (VUS) as benign or pathogenic variants in the context of HRD in tumors 6. In contrast, GPVs in other established and candidate BCSG genes such as ATM, ATR, BRIP1, MRE11, NBN, and RAD50 do not lead to BRCA-like tumors 6. We showed that inactivation of RAD51C, RAD51D, PALB2, and BARD1 are all associated with elevated Sig 3 levels, indicating that GPVs in these genes lead to BRCA-like/HRD cancers. The mutational signature analysis helped to define the role of various HR genes directly from case-only data by association with Sig 3 levels.
Monoallelic inactivation of BRCA1/2 does not give rise to Sig 3, whereas Sig 3 is seen in tumors with biallelically inactivated BRCA1/2. COSMIC tumor mutational signature 3 (Sig 3) has been associated with homologous repair deficiency (HRD) 8. We showed that using sequencing of paired tumor and normal tissues we can detect these HRD-associated mutational signatures as well as second hits 6, 7. In addition, in tumors with anomalies in HR repair, single base-pair changes have been shown to accumulate in the tumor genome, giving rise to what is referred to as mutational signatures. This observation led to the development of an HRD index based on these somatic genomic abnormalities that can be used to detect HRD implicated tumors rather than on the specific mutational spectrum at the nucleotide level of the altered the DNA sequence 2, 3, 4, 5. Tumor genomes of patients with BRCA1/2 inactivation were found to be enriched in copy number losses and rearrangements. In this tumor suppressor model of BCSG function, as a nascent tumor cell loses the ability to repair DNA, lesions accumulate, including in genes favoring tumor progression 1.
In BC cases due to known BCSGs, the inherited pathogenic variant confers genetic susceptibility, but tumorigenesis is usually driven by a somatic inactivating “second-hit” event resulting in loss of gene function, often via loss of heterozygosity (LOH) through deletion of the wild-type allele. We and others showed that tumor sequencing is a powerful tool to find genes or variants that cause HRD breast cancer.
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