Abstract
Breast cancer is one of the most frequently diagnosed cancers in both women and female dogs. Genome-wide association studies in human breast cancer (HBC) have identified hundreds of genetic variations and somatic driver mutations. However, only a handful of variants have been studied for rare HBC and their associations remain inconclusive. Spontaneous canine mammary tumor (CMT) is a great model for HBC, with clinical similarity. We thus performed whole-exome sequencing in 20 pairs of CMT and normal tissues in dogs. We newly found that PIK3CA was the most frequently mutated gene in CMT (45%). Furthermore, canine PIK3CA A3140G (H1047R), at what is known as the mutational hotspot of HBC, is also a hotspot in CMT. Targeted sequencing confirmed that 29% of CMTs had the same PIK3CA A3140G mutation. Integration of the transcriptome suggests that the PIK3CA (H1047R) induced cell metabolism and cell cycle via an increase of PCK2 and a decrease of CDKN1B but had no effect on cell apoptosis. We identified additional significantly mutated genes, including SCRN1 and CLHC1, which have not been reported in HBC. Our study recapitulated some known HBC-associated genes and human cancer signatures in CMT, and identified novel genes that may be relevant to HBC. This study may allow us to better understand both HBC and CMT and lend new insights into the development of biomarkers.
Highlights
Human breast cancer (HBC) affects one in four women worldwide [1]
Whole Exome Sequencing in canine mammary tumor (CMT) Was Performed
We demonstrated that PIK3CA mutations are key somatic driver mutations in CMTs just as in HBC [49]
Summary
It is well known that women who have a family history of HBC have an increased risk of developing HBC. Some high-penetrance mutations responsible for an increased risk of HBC have been found, such as BRCA1 and BRCA2, PTEN, RAD50, and TP53 [2]. Over the last few decades, together with the development of high-throughput sequencing technology, a huge number of genome-wide association studies (GWAS). GWAS data which revealed that silent mutations (synonymous mutations without amino acid changes) frequently contribute to various cancers [4]. This may suggest that HBC is a very complex disease and non-genetic factors, as well as the heterogeneity of human populations, need to be addressed and overcome to discover missing high-risk genes. Studies comparing matched tumor/normal pairs (T/N) have revealed many probable driver genes for HBC, including TP53 and PIK3CA, that are most frequently mutated [5,6]
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