by ecancer reporter Clare Sansom

Breast cancer is a heterogeneous disease both genetically and in terms of its prognosis.

Many breast cancers have a very good prognosis, and the ten-year survival rate for the disease as a whole in developed countries is over 80%. However, some breast cancers are still very difficult to treat. 

The genetic diversity of this disease is not yet completely understood; in particular, the full range of driver mutations – those somatic mutations in tumour tissue that can drive the process of oncogenesis – has not yet been identified.

A large, international group of researchers led by Michael Stratton and his team at the Wellcome Trust Sanger Institute, Hinxton, UK has now conducted an extensive study of the genetic diversity of breast cancer.

The researchers sequenced the complete coding regions of the genomes, or the exomes, from 100 primary breast tumours and normal tissue from the same patients.

Seventy-nine of the tumours were oestrogen receptor positive (ER⁺) and the remaining 21 oestrogen receptor negative (ER^-).

The sequences of a total of 21,416 protein-coding genes and 1,664 micro-RNAs were examined for somatic point mutations, small insertions and deletions and copy number changes.

A large number of genetic changes were identified, including 4,737 point mutations predicted to generate missense mutations; 422 nonsense mutations (premature stop codons); 1.712 homozygous deletions and 1,751 regions with increased copy number. The number of mutations present in the individual tumours was extremely variable with a total of 73 different combinations of mutated genes observed in this study population.

The researchers then searched for clusters of somatic mutations in known protein-coding genes and sequenced each of the resulting candidate genes in an independent follow-up series of 250 breast tumours. This highlighted at least 40 genes from the original set that were mutated in sufficient tumours for the mutations to be thought likely to act as drivers of carcinogenesis.

This gene set included nine that had not previously been identified as carriers of driver mutations in breast cancer. Truncating and therefore inactivating mutations were found in seven of these – ARID1B, CASP8, MAP3K1, MAP3K13, NCOR1, SMARCD1 and CDKN1B – indicating that these are likely to be tumour suppressor genes. Mutations in AKT2 were thought to be activating, and the mechanism through which TBX3 mutations lead to cancer could not be determined.

Two of these newly identified driver genes, MAP3K1 and MAP3K13, encode serine / threonine protein kinases that are known to phosphorylate and activate other kinases in the JUN signaling pathway.

Inactivating mutations in these genes prevent the activation of JUN kinase, a transcription factor that, like the “guardian of the genome” TP53, modulates the cellular stress response. The single gene with identified mutations thought to be activating, AKT2, also encodes a serine / threonine protein kinase; a point mutation in this gene identified in a number of tumours is equivalent to one already known to activate the related kinase gene AKT1 in breast cancer.

Truncating mutations and deletions were also observed in NCOR1, SMARCD1, CASP8 and CDKN1B. CDKN1B, which has previously been implicated in the development of some other tumour types, encodes an inhibitor of the cyclin dependent kinases CDK2 and CDK4 and is therefore involved in the control of the cell cycle. NCOR1 and SMARCD1 encode proteins that are involved in regulating of chromatin and therefore access to the machinery of gene transcription, and the final potential tumour suppressor gene identified in this study, CASP8, encodes a caspase: a protease that promotes apoptosis in response to cellular signals.

Although none of these genes had previously been identified as carriers of driver mutations in breast cancer, common variants in MAP3K1, CASP8 and TBX3 have been identified in genome wide association scans as conferring small increased risks of the disease.

Taken together, these results confirm the enormous genetic heterogeneity of breast cancer, identify nine further genes as important in carcinogenesis in some breast tumours, and provide an important contribution to the developing map of the genetics of this common disease.

Reference

Stephens, P.J., Tarpey, P.S., Davies, H. and 64 others (2012). The landscape of cancer genes and mutational processes in breast cancer. Nature, published online ahead of print 16 May 2012. doi:10.1038/nature11017