89PPan-cancer genomic analysis of MSI-H tumors reveals commonly altered pathways

Background: Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency and can be attributed to alterations in MMR-related genes including MSH2, MLH1, MSH6, and PMS2. Although alterations in PI3K pathway genes have been reported in MSI-High (MSI-H) colorectal carcinoma (CRC), a comprehensive enrichment analysis of the genomic landscape in MSI-H and MSI-stable (MSS) populations across tumor types is lacking. To better understand the molecular signatures of MSI and investigate new avenues for therapeutic opportunities, we sought to define the genomic landscape of MSI-H tumors across cancer types. Methods: Comprehensive genomic profiling of 395 cancer-related genes, including MSI status, was performed on ∼70,000 tumors. To identify potential driver alterations enriched in MSI-H tumors, variants in regions likely to be affected by polymerase slippage were excluded. Results: As expected, alterations in MSH2, MHL1, MSH6, and PMS2 as well as MMR deficiency variants were enriched in MSI-H specimens regardless of tumor type. We confirmed that variants in PI3K genes were enriched in MSI-H tumors in CRC. Importantly, this was observed across all MSI-H tumors, with 57% of pan-solid MSI-H tumors harboring a PI3K pathway variant compared to 24% of MSS tumors. WNT pathway variants were also enriched specifically in MSI-H tumors, except for CRC, in which frequent APC variants in MSS resulted in WNT enrichment in MSS tumors. Together, 84% of MSI-H tumors have at least one PI3K or WNT pathway variant (compared to 48% of MSS samples). Finally, although ERBB2 alterations occur in both MSS and MSI-H tumors, we found that ERBB2 amplifications occur nearly exclusively in MSS tumors, while ERBB2 missense mutations are enriched in MSI-H tumors. Conclusions: The genomic landscapes of MSI-H and MSS tumors suggest that they acquire alterations in distinct pathways. MSI-H tumors appear to share signaling pathway alterations across diseases, suggesting that MSI-H tumors may be more molecularly similar to one another than they are to MSS tumors of the same disease histology. These data may provide new avenues for exploration of targeted therapies in MSI-H tumors. Legal entity responsible for the study: Foundation Medicine Inc. Funding: Foundation Medicine Inc. Disclosure: S.E. Trabucco: Current employee at Foundation Medicine. S.L. Maund, P.S. Hegde, S-M.A. Huang: Current employee and has ownership interest in Genentech. R. Hartmaier, K. Gowen, KJ. Sun, G.M. Frampton, P.J. Stephens: Current employee and has ownership interest in Foundation Medicine.