Abstract
Cancer is believed to be a result of accumulated mutations. However, this concept has not been fully confirmed owing to the impossibility of tracking down the ancestral somatic cell. We sought to verify the concept by exploring the correlation between cancer risk and mutation accumulation among different tissues. We hypothesized that the detected mutations through bulk tumor sequencing are commonly shared in majority, if not all, of tumor cells and are therefore largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor. We collected a comprehensive list of mutation frequencies revealed by bulk tumor sequencing, and investigated its correlation with cancer risk to mirror the correlation between mutation accumulation and cancer risk. This revealed an approximate 1:1 relationship between mutation frequency and cancer risk in 41 different cancer types based on the sequencing data of 5,542 patients. The correlation strongly suggests that variation in cancer risk among tissues is mainly attributable to distinct mutation accumulation rates. Moreover, the correlation establishes a baseline to evaluate the effect of non-mutagenic carcinogens on cancer risk. Finally, our mathematic modeling provides a reasonable explanation to reinforce that cancer risk is predominantly determined by the first rate-limiting mutation.
Highlights
The availability of the whole genome sequencing data of bulk tumor tissues[13], presents an opportunity to evaluate the mutation rate of the ancestral somatic cell of each tumor
The mutation frequencies of 41 different cancer types from the data of 5,542 human tumors detected by whole genome/exome sequencing were collected (Supplementary Text and Supplementary Table1)
When the mutation rate of the same cancer type is increased by mutagens or hereditary defects (i.e., HNPCC vs. MSI-Colorectal cancer, MSS-stomach cancer vs. MSI-stomach cancer), the lifetime incidence rises in a corresponding rate. Another example is the most common type of human cancers – skin cancers including melanoma, squamous and basal cell carcinoma[18], for which our result suggests that the differences in cancer incidence match the variation of mutation frequency
Summary
The availability of the whole genome sequencing data of bulk tumor tissues[13], presents an opportunity to evaluate the mutation rate of the ancestral somatic cell of each tumor. The mutations revealed by bulk tumor sequencing are largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor (see Supplementary Text for more discussions). This supposition is strongly supported by the finding that half or more of the mutations detected in tumor bulk occur prior to tumor initiation, that is, during the growth of normal cells[1,17]. Investigating the correlation between mutation accumulation in tumor bulk and cancer risk can be an alternative way to mirror the correlation between mutation rate in somatic cells and cancer risk
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