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Cancer Exome Data Points to Key Pathways Altered By Driver Mutations

By Andrea Anderson

WASHINGTON, DC (GenomeWeb News) – Although a wide range of genes are mutated in cancer, the apparent driver mutations identified so far fall into relatively few molecular pathways, according to Johns Hopkins University cancer researcher Bert Vogelstein.

Speaking at a plenary session on the cancer genome at the American Association for Cancer Research annual meeting here yesterday, Vogelstein said data from 100 cancer exome sequences suggests the coding mutations that drive cancer development and progression fall in only about a dozen key pathways.

His presentation was based on data gleaned from 100 exome or whole-genome sequencing projects. Among them: published exome and/or genome sequencing studies on 78 cancers (including work by Johns Hopkins researchers on 11 colorectal cancers, 11 breast cancers, 24 pancreatic adenocarcinomas, and 22 gliomas) and another 22 unpublished medulloblastoma exomes sequenced by Vogelstein and his colleagues.

For example, Vogelstein explained, pancreatic cancer genes harbor between about 30 and 60 non-silent point mutations (with a median of 44 non-silent coding mutations), as well as additional changes such as amplifications and deletions that bring the coding mutation tally up to a median of about 63 alterations per tumor.

Meanwhile, he said, breast, colorectal, and brain cancers have around 30 to 80 non-silent coding mutations, while melanoma and lung cancers — which typically involve exposure to environmental mutagens — harbor about twice as many.

Nevertheless, data from cancer coding sequences suggests most mutations in tumor exomes represent passenger mutations, Vogelstein told AACR attendees. Of the more than 130,000 somatic, intragenic mutations identified in tumors, he explained, just 319 of the 3,142 affected genes appear to contain driver mutations.

In addition, Vogelstein said, 286 — or nearly 90 percent — of genes affected by the known or suspected driver mutations appear to be tumor suppressor genes, while just 33 genes are potential oncogenes. Nearly all of these driver mutations are components of 12 core pathways, such as the TGF-beta signaling, apoptosis, or DNA damage pathways.

While the repertoire of mutated genes and types of mutations can vary dramatically from one tumor to the next, the pathways affected by cancer driver mutations are increasingly well understood, he argued.

Although tumor heterogeneity is still a challenge and more sequencing will likely uncover additional driver and passenger mutations, Vogelstein predicts that the driver mutations identified in coding sequences down the road will also belong to many of the same key pathways.

Along with the need for more functional studies in human cancer cells, including affected cell types, Vogelstein highlighted the importance of translating cancer exome and genome data into new cancer treatment and detection strategies.

In particular, based on findings from exome sequencing studies, he noted that pathway-targeted therapies as well as gene-targeted therapies will likely be needed to target driver mutations — particularly those affecting apparent tumor suppressor genes that can't be inhibited by drugs to treat cancer.

"The challenge is how to use this knowledge to help people," Vogelstein said, urging young investigators to be creative and begin coming up with new therapeutic and early detection strategies even as researchers continue decoding and deciphering cancer genomes and exomes.

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