Discovery and saturation analysis of cancer genes across 21 tumor types

Nature (Impact Factor: 41.46). 01/2014; 505(7484). DOI: 10.1038/nature12912
Source: PubMed


Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.

149 Reads
  • Source
    • "To perform the search, students identified and selected a cancer type in which p300 was found to be significantly mutated using [22]. Students then used the COSMIC database to identify missense mutations in the p300 bromodomain that have been found in endometrial cancers (see Supporting Information File 2, Week 1). "

    Biochemistry and Molecular Biology Education 11/2015; DOI:10.1002/bmb.20927 · 0.65 Impact Factor
  • Source
    • "Genes affected by non-passenger mutations were further annotated using FATHMM (Shihab et al., 2013) and according to their presence in three cancer gene datasets: Cancer Gene Census (Futreal et al., 2004), 127 genes by Kandoth et al. (Kandoth et al., 2013) and the Cancer-5000S dataset by Lawrence et al. (Lawrence et al., 2014). " Lollipop plots " showing the distribution of mutations were generated using Mutation- Mapper on cBioPortal ( "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing. Methods DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches. Results The constellation of somatic mutations found in LCIS (n = 34) and ILC (n = 21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1). Conclusion LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS–LCIS and LCIS–ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC.
    Molecular Oncology 11/2015; DOI:10.1016/j.molonc.2015.11.001 · 5.33 Impact Factor
  • Source
    • "However, not all of these mutations prove to be relevant for malignancy. Melanomas have a median of 13‐17 mutations per Mbp of DNA, the highest frequency among 21 cancer types analyzed (The Cancer Genome Atlas Network, 2015; Hodis et al., 2012; Lawrence et al., 2014), even without considering rearrangements, copy‐number alterations and epigenetic changes. These mutations predominantly carry the signature of ultraviolet light mutagenesis (Hodis et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are many links between cell senescence and the genetics of melanoma, meaning both familial susceptibility and somatic-genetic changes in sporadic melanoma. For example CDKN2A, the best-known melanoma susceptibility gene, encodes two effectors of cell senescence, while other familial melanoma genes are related to telomeres and their maintenance. This article aims to analyze our current knowledge of the genetic or epigenetic driver changes necessary to generate a cutaneous metastatic melanoma, the commonest order in which these occur and the relation of these changes to the biology and pathology of melanoma progression. Emphasis is laid on the role of cell senescence and the escape from senescence leading to cellular immortality, the ability to divide indefinitely.This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 09/2015; DOI:10.1111/pcmr.12422 · 4.62 Impact Factor
Show more

Preview (4 Sources)

149 Reads
Available from