Mutational landscape and significance across 12 major cancer types

Abstract

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(forexample, mitogen-activatedprotein kinase, phosphatidylinositol-3-OH kinase,Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the numberof driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

The landscape of genomic alterations across childhood cancers

“…In this cohort, hypermutation occurred exclusively in H3.3 or H3.1 K27-wildtype (K27wt) high-grade gliomas with biallelic germline mutations in MSH6 or PMS2, with an extremely high mutational burden similar to the highest among adult tumours (in POLE-or POLQ-mutated carcinomas) 7,12 (Fig. 1).…”

“…1b, c). Mutation frequencies varied between cancer types (0.02-0.49 mutations per Mb) and were overall 14 times lower than in adult cancers 7 (0.13 versus 1.8 mutations per Mb, TCGA data; Table 3). Relapse tumours harboured significantly more mutations than primary tumours (P = 0.0015, excluding highly mutated tumours; Extended Data Fig.…”

“…A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets.…”

“…We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets.…”

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…1 –5 Increasing tumor mutational burden (TMB) and the generation of neoepitopes have been associated with immunogenicity in several tumor types. 6,7 TMB is associated with clinical benefit to immune checkpoint blockade in patients with melanoma, lung, and colon cancer. 8–11 The role of TMB in tumor immunogenicity is less clear in breast cancer.…”