Somatic mutations in cancer
Many ABC genes are efflux transporters involved in the resistance to multiple chemotherapy drugs. However, there are no ABC transporters amongst the 299 documented frequently mutated genes, or driver genes, in cancer (Bailey et al., 2018). Therefore, to determine the potential role of somatic mutations in ABC genes in cancer, we tabulated the number and class of modifications along with the rate of gene amplification, overexpression, or gene fusion (Supplementary Table 3 ).
Nearly all ABC genes have low levels of somatic mutations and no observed gene fusions. The most frequently mutated ABC gene in cancer isABCA13 , but this is a large gene with low expression and late replication timing. However, neither ABCA13 nor any other ABC gene passes the criteria for a significantly mutated gene in cancer. Common recurrent missense mutations are found in many oncogenes and are usually associated with a gain of function. There are a few common recurrent mutations such as p.R1476Q in ABCA5 , p.S422F inABCC7/CFTR , and p.S606P and p.G608D in ABCD1 . TheABCD1 mutations are found primarily in lung cancer and the conserved LSGG motif in the ATP-binding domain. This data suggests that ABCD1 may play a role in a subset of lung malignancies.
Several ABC genes have frequent copy number gains (>10%) in specific cancers. The amplifications include ABCB10 in liver cancer, ABCC4 in colon cancer, ABCC9 in testicular cancer, and ABCC5 and ABCF3 in cervical cancer. The role of these events in these cancers is unknown, although ABCF3 is overexpressed in cervical cancer (Choi et al., 2007). In addition, there is an elevated expression of many ABC genes >30% of specific tumors. For example, ABCA7 and ABCC8 expressed are high in 33% of adrenal tumors, ABCC5 in 45% of esophageal cancers, and ABCF3 in 45% of cervical cancers. Whether these over-expressed genes contribute to drug resistance or other phenotypes of these cancers remains undetermined.