Key Points
-
We have conducted a census from the literature of genes that are mutated and causally implicated in cancer development ('cancer genes').
-
So far, 291 cancer genes have been reported, more than 1% of all the genes in the human genome.
-
90% of cancer genes show somatic mutations in cancer, 20% show germline mutations and 10% show both.
-
The most common mutation class among the known cancer genes is a chromosomal translocation that creates a chimeric gene or apposes a gene to the regulatory elements of another gene.
-
Many more cancer genes have been found in leukaemias, lymphomas and sarcomas than in other types of cancer, despite the fact that they represent only 10% of human cancer. These genes are usually altered by chromosomal translocation.
-
The most common domain that is encoded by cancer genes is the protein kinase. Several domains that are involved in DNA binding and transcriptional regulation are common in proteins that are encoded by cancer genes.
Abstract
A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Reddy, E. P., Reynolds, R. K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).
Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982). References 1 and 2 are seminal papers that defined the existence of oncogene sequences in cancer-cell genomes and that first identified a mutation involved in human cancer.
Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).
Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).
Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).
Merlo, A. et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med. 1, 686–692 (1995).
Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).
Baylin, S. & Bestor, T. H. Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1, 299–305 (2002).
Duval, A. & Hamelin, R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 62, 2447–2454 (2002).
Duval, A. et al. Evolution of instability at coding and non-coding repeat sequences in human MSI-H colorectal cancers. Hum. Mol. Genet. 10, 513–518 (2001).
Grady, W. M. et al. Mutational inactivation of transforming growth factor β receptor type II in microsatellite stable colon cancers. Cancer Res. 59, 320–324 (1999).
Ohta, M. et al. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84, 587–597 (1996).
Bednarek, A. K. et al. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res. 60, 2140–2145 (2000).
Sutherland, G. R., Baker, E. & Richards, R. I. Fragile sites still breaking. Trends Genet. 14, 501–506 (1998).
Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1946 (1997).
Laken, S. J. et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nature Genet. 17, 79–83 (1997).
Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet. 31, 55–59 (2002).
Shih, C., Shilo, B. Z., Goldfarb, M. P., Dannenberg, A. & Weinberg, R. A. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc. Natl Acad. Sci. USA 76, 5714–5718 (1979).
Krontiris, T. G. & Cooper, G. M. Transforming activity of human tumor DNAs. Proc. Natl Acad. Sci. USA 78, 1181–1184 (1981).
Baker, S. J. et al. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 50, 7717–7722 (1990).
Hwang, S. -J., Lozano, G., Amos, C. I. & Strong, L. C. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am. J. Hum. Genet. 72, 975–983 (2003).
Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).
Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002).
Futreal, P. A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122 (1994).
Lancaster, J. M. et al. BRCA2 mutations in primary breast and ovarian cancers. Nature Genet. 13, 238–240 (1996).
Nikiforov, Y. E. RET/PTC rearrangement in thyroid tumors. Endocr. Pathol. 13, 3–16 (2002).
Kroll, T. G. et al. PAX8–PPARγ1 fusion in oncogene human thyroid carcinoma. Science 289, 1357–1360 (2000).
Sidhar, S. K. et al. The t(X;1)(p11. 2;q21. 2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum. Molec. Genet. 5, 1333–1338 (1996).
Tognon, C. et al. Expression of the ETV6–NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2, 367–376 (2002).
Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
Eng, C. & Mulligan, L. M. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and Hirschsprung disease. Hum. Mutat. 9, 97–109 (1997).
Wong, A. J. et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc. Natl Acad. Sci. USA 89, 2965–2969 (1992).
Zhuang, Z. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genet. 20, 66–69 (1998).
Bongarzone, I. et al. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RIα of cyclic AMP-dependent protein kinase A. Molec. Cell. Biol. 13, 358–366 (1993).
Kirschner, L. S. et al. Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex. Nature Genet. 26, 89–92 (2000).
Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 30, 276–280 (2002).
Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).
Howe, J. R. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genet. 28, 184–187 (2001).
Gilliland, D. G. & Griffin, J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood 100, 1532–1542 (2002).
Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
Heinrich, M. C. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299, 708–710 (2003).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
Cancer.gov
LocusLink
OMIM
FURTHER INFORMATION
Glossary
- CpG ISLANDS
-
GC-rich areas of the genome, usually of the order of a kilobase in size, often in and around the 5′ regions of genes, which retain an unusually high number of CpG dinucleotides.
- PASSENGER OR BYSTANDER MUTATIONS
-
Somatic mutations that are found in cancer cells that are not involved in generating the neoplastic phenotype.
- MYXOMA
-
A rare type of tumour that is usually composed of sparse mesenchymal cells interspersed amid large amounts of intercellular material.
Rights and permissions
About this article
Cite this article
Futreal, P., Coin, L., Marshall, M. et al. A census of human cancer genes. Nat Rev Cancer 4, 177–183 (2004). https://doi.org/10.1038/nrc1299
Issue Date:
DOI: https://doi.org/10.1038/nrc1299