The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

Abstract

We propose that initiating truncal mutations plays a special role in tumor formation by both enhancing the survival of the initiating cancer cell and by selecting for secondary mutations that contribute to tumor progression, and that these mutations often act in a tissue-preferred fashion. Here, we explain why inherited mutations often have different tissue specificities compared with spontaneous mutations in the same gene. Initiating truncal mutations make excellent neo-antigens for immunotherapy, and understanding why one mutation selects for a second mutation in a particular tissue type could one day aid in the design of genetargeted combination therapies. PerspectiveMost cancers develop over time, accumulating a series of mutations that combine to produce a malignant tumor. As a consequence, most cancers in humans occur later in life, with a steep increase in their frequencies approximated by the binomial equation I(t) = kt rÀ1 , where I is the incidence as a function of time, k is a constant that depends upon the lifespan of the species, t is time, and r is a function of the number of mutations it takes to form the cancer (Armitage and Doll, 1954). If the first mutation in the series is inherited, the curve giving the age of the onset of tumors in a population shifts to the left or younger ages, indicating the critical role of r or mutation number. As mutations accumulate, they frequently occur in different functional pathways that regulate genomic stability, metabolic processes, cell-cycle regulation, epigenetic stability, immunological detection, etc., in a list that has come to be recognized as the hallmarks of cancer Weinberg, 2000, 2011).The first recognition that the order of mutations occurring in a cancerous precursor cell was an important variable and even determined the nature of the subsequent mutations that gave rise to the cancer was appreciated by Bert Vogelstein and colleagues in a series of papers studying colorectal cancer (CRC) in humans. Vogelstein's laboratory took advantage of the fact that this cancer develops in stages over time, starting with benign small-sized polyps, which, with further time, develop into larger benign polyps and eventually malignant colorectal carcinomas (Nigro et al., 1989;Baker et al., 1990aBaker et al., , 1990b. By taking samples from these different stages using colonoscopy and sequencing the DNA, they appreciated that CRC develops through the stepwise selection of genetic changes. The initiating or gatekeeping mutation was primarily biallelic loss of APC, which occurs in >80% of cases, or at a lower frequency the b-catenin gene (CTNNB1) in the same WNT signaling pathway. Subsequent activating mutations in KRAS were identified in early-to-intermediate adenoma-stage tumors, while loss-offunction mutations in SMAD4 were identified in large adenomas. Finally, the loss of p53 functions resulted in a malignant adeno-carcinoma. Large-scale CRC genome-sequencing studies also identified numerous infrequently mutated genes in CRC, in addition to the commonly mutated AP...

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