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Pan-Cancer Analysis Identifies Targets for Personalized Medicine

NEW YORK (GenomeWeb) – A team led by researchers at Baylor College of Medicine has uncovered a number of mutations in a pan-cancer analysis that it said could be used as targets for tailored treatments.

Using data from the Cancer Genome Atlas, the researchers examined molecular alterations affecting the PI3K/AKT/mTOR pathway in more than 11,000 cancers from 32 tumor types. The PI3K/AKT/mTOR pathway is a growth regulatory pathway that is often activated in cancer.

As the team reported yesterday in Cancer Cell, it used whole-genome sequencing, whole-exome sequencing, copy number, and proteomic data from TCGA to home in on molecular changes affecting the PI3K/AKT/mTOR pathway that are likely functional.

"PI3K is the most commonly mutated pathway in cancer that can be targeted by drugs," co­author Gordon Mills, professor of medicine and immunology at MD Anderson Cancer Center, said in a statement. "Thus, understanding how the pathway and mutations in cancer affect the many different cancer lineages is important."

The researchers gathered 11,219 human cancer cases — representing 32 major types of cancer — for which the TCGA had generated data using one or more molecular approaches.

The proteomic data gathered via reverse-phase protein arrays covered more than 7,600 samples from 31 cancer types. By considering the PI3K/AKT and mTOR pathway branches separately, the researchers generated pathway signatures for each, which they then summarized into activity scores. While PI3K/AKT and mTOR scores generally correlated across tumor profiles, the researchers noted that they didn't always, suggesting that there is some decoupling between the two branches of the pathway.

Using the sequencing and somatic DNA copy number alteration data, Mills and his colleagues identified a number of genes within the PI3K/AKT/mTOR pathway that were significantly mutated or copy-number altered in a pan-cancer analysis. Mutations commonly affected PIK3CA, PTEN, and PIK3R1, they reported, noting that most copy number changes correlated with changes in mRNA expression. Meanwhile, genomic rearrangements commonly affected PTEN, INPP4B, and STK11. They also noted roles for IDH1 and VHL mutations in mTOR activation, neither of which had been linked to the pathway in cancer.

However, Mills and his colleagues also found that a large number of mutations in genes that activate the PI3K/AKT/mTOR pathway occurred only occasionally. For instance, they noted that while most PIK3CA mutations occur at three known positions, some 13 percent of PIK3CA mutations were only observed once.

For a portion of genes, including PIK3CA, PTEN, PIK3R1, and MTOR, the researchers sifted through mutations to separate them based on whether or not they were predicted to be functional by residue hotspot, literature review, or by nonsense, frameshift, or indel changes. Tumors containing mutations they considered to be functional had higher phospho-AKT levels, on average, suggesting that they activated AKT.

By folding in cell-based functional assays, the researchers found that, for PIK3CA and PIK3R1, variants associated with functionality in vitro occurred at a higher frequency in human tumors.

Alterations affecting members of the PI3K/AKT/mTOR pathway were also significantly associated with patient outcomes in a pan-cancer analysis, Mills and his colleagues reported. For instance, they noted that STK11 mutation or copy loss, PTEN copy loss, and PIK3CA amplifications were all associated with worse patient outcome, regardless of cancer type.

They said that stratifying patients by mutation status — such as ones affecting PI3K3CA — could increase response rates in clinical trials examining PI3K/AKT/mTOR pathway inhibitors and move along personalized medicine.

"The comprehensive nature of this project that integrates information from multiple levels has the potential to impact patient management and to eventually improve outcomes for the large population of patients with abnormalities in this very important pathway," Mills added.