Comparative analysis of germline and somatic micro-lesion mutational spectra in 17 human tumour suppressor genes

The known somatic (N>4000) and germline (N>4000) cancer-associated mutational spectra (viz. missense and nonsense mutations micro-deletions, micro-insertions and micro- indels <20bp) of 17 human tumour suppressor genes (viz. APC, ATM, BRCA1, BRCA2, CDH1, CDKN2A, NF1, NF2, PTCH, PTEN, RBI, STK11, TP53, TSC1, TSC2, VHL and WT1) were compared in order to identify similarities and differences. Analysed parameters included the recurrence status of mutations, CpG mutability Grantham difference evolutionary conservation of affected codons role of nonsense-mediated mRNA decay and co-location with repetitive sequence elements. Only a small proportion of the mutations (-5%) were found to be shared between the germline and soma, although the proportions varied between different types of mutation (from 11% for missense mutations to 1% for micro-indels). Shared mutations are unlikely to be coincidental and are probably indicative of underlying shared (and endogenous) mutational mechanisms. Shared missense mutations were found to be more likely to be drivers of tumorigenesis than either exclusively somatic or exclusively germline missense mutations. Shared micro-lesions combined for all genes occurred disproportionately within repetitive elements by comparison with both somatic or germline micro-lesions, consistent with an endogenous mutational mechanism. For some genes (e.g. TP53), shared CpG-dinucleotide mutations evidenced the action of an endogenous mutational mechanism (viz. methylation-mediated deamination of 5-methylcytosine) in both the soma and the germline. Differences between mutational spectra were also noted. Germline missense mutations were found to be more likely to bear relatively more drastic functional consequences by comparison with somatic missense mutations, but also more likely to be truncating mutations. Germline micro-lesions (combined for all genes) were also found to be more likely to be co-located with repetitive elements than somatic micro-lesions. This could be due to the germline being relatively more protected from the action of exogenous mutagens by comparison to the soma. This study of 17 human tumour suppressor genes has therefore provided a first glimpse of the similarities and differences between germline and somatic mutational spectra