Mutational Landscape of Metastatic Cancer Revealed from Prospective Clinical Sequencing of 10,000 Patients

By A. Zehir, R. Benayed, Ronak H. Shah, Aijazuddin Syed, Sumit Middha, H. R. Kim, P. Srinivasan, Jianjiong Gao, D. Chakravarty, S. Devlin and 90 more. Nature Medicine, 2017

2,983 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/0a2cc8278e64eed3a0686bd57b86e7c8ba7ff4b3

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Citations in the corpus

Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “, 2015), and a pan-cancermetastasis study (Zehir et al., 2017), where mutations in these same genes are also acquired late in disease evolution.”
Molecular profiling for precision cancer therapies (2020, neutral): “MSKCC [27] 12,670 341–410 gene panels FFPE Yes 527/5009 (10.”
Clinical sequencing defines the genomic landscape of metastatic colorectal cancer (2018, background): “This somatic intronic mutation was specific to MSS CRC, as we did not identify the mutant allele in any other tumor type analyzed by MSK-IMPACT (n = 9,939) (Zehir et al., 2017).”
A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) (2018, background): “Consequently, more and more patients undergo multigene sequencing of their cancer in the hope of finding genomic alterations that could effectively be targeted with matched drugs [2].”
A foundation model for clinical-grade computational pathology and rare cancers detection (2024, neutral): “…sections matching the blocks used for DNA extraction and MSK-integrated mutation profiling of actionable targets (MSK-IMPACT) sequencing 50 , the latter of which was analyzed to determine the status of genetic alterations and establish a binary label indicating the presence or absence…”
Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, methodology): “By contrast, the use of targeted NGS to guide treatment has become increasingly routine, particularly in patients with lung cancer.(15,16,35) Furthermore, consistent with recent reports that analyzed the same patient tumors for targeted NGS and WES,(15,35) we found that TMB quantified by targeted NG”
MOLI: multi-omics late integration with deep neural networks for drug response prediction (2019, background): “Presently, only 11% of patients treated with precision oncology can be placed in clinical trials and only 5% of patients benefit from precision oncology (Zehir et al., 2017; Cheng et al., 2018; Marquart et al., 2018).”
Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens (2019, positive): “Most patients however do not benefit from such targeted therapies in part due to limited knowledge of candidate targets(Zehir et al. 2017).”
A decade of clinical development of PARP inhibitors in perspective (2019, background): “As interest has evolved beyond gBRCA1/2 mutations, multiplexed NGS assays of both germline and somatic DNA have become the preferred tool for patient identification [53, 54].”
Oncogenic Signaling Pathways in The Cancer Genome Atlas (2018, background): “Asmore genetic alterations become targetable by specific drugs, DNA sequencing is becoming part of routine clinical care (Hartmaier et al., 2017; Schram et al., 2017; Sholl et al., 2016; Zehir et al., 2017).”