Details

Autor(en) / Beteiligte

• Berger, Alice H.
• Brooks, Angela N.
• Wu, Xiaoyun
• Shrestha, Yashaswi
• Chouinard, Candace
• Piccioni, Federica
• Bagul, Mukta
• Kamburov, Atanas
• Imielinski, Marcin
• Hogstrom, Larson
• Zhu, Cong
• Yang, Xiaoping
• Pantel, Sasha
• Sakai, Ryo
• Watson, Jacqueline
• Kaplan, Nathan
• Campbell, Joshua D.
• Singh, Shantanu
• Root, David E.
• Narayan, Rajiv
• Natoli, Ted
• Lahr, David L.
• Tirosh, Itay
• Tamayo, Pablo
• Getz, Gad
• Wong, Bang
• Doench, John
• Subramanian, Aravind
• Golub, Todd R.
• Meyerson, Matthew
• Boehm, Jesse S.

Titel

High-throughput Phenotyping of Lung Cancer Somatic Mutations

Ist Teil von

• Cancer cell, 2016-08, Vol.30 (2), p.214-228

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer. [Display omitted] •Expression-based phenotyping distinguishes neutral from impactful mutations•92% of missense mutations in KEAP1 and STK11 diminish gene function•Rare variants in ARAF, BRAF, EGFR, ERBB2, KRAS, and RIT1 are oncogenic•Erlotinib resistance induced by rare variant mutations is MEK dependent Berger et al. develop an expression-based variant-impact phenotyping method to distinguish impactful from neutral somatic mutations. The method identified rare gain-of-function mutations in oncogenes and widespread inactivation of tumor suppressors by missense variation. Variants of ARAF, BRAF, EGFR, ERBB2, KRAS, and RIT1 are shown to be oncogenic and to induce MEK-dependent resistance to EGFR inhibition.