Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12

AUTHORS

Jason Roszik, Lauren E. Haydu, Kenneth R. Hess, Junna Oba, Aron Y. Joon, Alan E. Siroy, Tatiana V. Karpinets, Francesco C. Stingo, Veera Baladandayuthapani, Michael T. Tetzlaff, Jennifer A. Wargo, Ken Chen, Marie-Andrée Forget, Cara L. Haymaker, Jie Qing Chen, Funda Meric-Bernstam, Agda K. Eterovic, Kenna R. Shaw, Gordon B. Mills, Jeffrey E. Gershenwald, Laszlo G. Radvanyi, Patrick Hwu, P. Andrew Futreal, Don L. Gibbons, Alexander J. Lazar, Chantale Bernatchez, Michael A. Davies, Scott E. Woodman

ABSTRACT

BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer. More... »

PAGES

168

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12916-016-0705-4

DOI

http://dx.doi.org/10.1186/s12916-016-0705-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1051992805

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27776519


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