MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy. Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types. We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8+ T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number. Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

In addition to guiding therapy, simultaneous DNA sequence analysis of tumor-normal pairs (“tumor-normal sequencing”) reveals inherited cancer predisposition mutations in 3% to 12.6% of pediatric and adult patients with cancer.^1-7 It remains unknown, however, how many inherited mutations would be detected by multigene tumor-normal analysis compared with a traditional family history–based approach to genetic counseling and testing, and what the clinical implications of these findings would be. Selection for genetic testing is traditionally based on pathologic features of the tumor, age at diagnosis, family history of cancer, and other factors represented in clinical practice guidelines.^8-10 Studies have not determined whether inherited mutations found by tumor-normal sequencing would have been detected by traditional approaches to selection for genetic testing.^1-5