by ecancer reporter Clare Sansom

Comprehensive analyses of mutation patterns in human tumours is essential for a full understanding of the biochemical processes underlying the disease, but the scale of these has so far been limited by the sequencing technology available to either a small number of samples or a small number of genes.

Now, however, a large group of researchers from Genentech, Affymetrix and Pennsylvania State University has used the novel technology of mismatch repair detection (MRD)* to analyse regions of DNA that include over 1,500 putative protein-coding genes in samples from 441 tumours. The tumours studied were mainly breast, ovarian, lung and prostate cancers with different genetic profiles; the genes included many known to be linked with cancer or otherwise believed to be useful drug targets.

In total, 2,576 somatic mutations were identified in this range of tumour samples, and just under two-thirds – 967 – of the genes were found to be mutated in at least one tumour. Most of these mutations had not previously been reported as associated with cancer. Eighty-five percent of the tumours carried at least one protein-altering mutation in one of the studied genes; lung adenocarcinomas and squamous cell carcinomas appeared to carry the most, and prostate cancers the fewest, mutations.

A total of 77 of the genes studied were found to have a high and statistically significant prevalence of cancer-related mutations. The set of “significantly mutated” genes varied between cancer types and even between subtypes, indicating the genetic heterogeneity of cancer development. Mutations were particularly common in members of two gene families that are known to be closely linked to cancer (and that were therefore well represented in the sample of genes studied): the G-protein coupled receptors (GPCRs) and the kinases. Many of these proteins are known to be involved in signal transduction pathways that are known to be disrupted in cancer, including the JNK pathway. Further analysis confirmed the tumour suppressor role of one significantly mutated kinase in this pathway, MAP2K4.

Combining gene sequence analysis with copy number analysis identified a further thirty-five additional cancer-associated genes. These included GNAS, a gene coding for the G-protein alpha subunit, which was found to be mutated or amplified in many tumour samples. Another G-alpha gene, GNAO1, was found to be mutated at structurally important positions. Several known tumour suppressor genes showed significant copy number loss.

This study confirms and extends the diversity of mutations known to occur in all tumour subtypes studies. This, the authors conclude, shows that “each tumour is unique even within a given type and subtype”. They suggest that understanding this diversity will allow more sophisticated patient stratification, paving the way for personalised medicine. 

Article:

Kan, Z., Jaiswal, B.S., Stinson, J. and 29 others (2010). Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869-873. doi: 10.1038/nature09208