RAS precision medicine trans-Atlantic partnership: Multi-centre analysis of RAS and NF1 co-mutations in advanced NSCLC
Krebs, Matthew G
Blackhall, Fiona H
Lindsay, Colin R
AffiliationDepartment of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
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AbstractBackground RAS mutations are the most common oncogenic drivers in adenocarcinoma. KRAS is mutated in ?30% of non-small cell lung cancer (NSCLC), majority of pancreatic adenocarcinomas and ?40% of colorectal cancers (CRC). NF1 encodes the RAS GAP neurofibromin, functioning as an inhibitor of the MAPK pathway by facilitating the hydrolysis of RAS to its GDP-bound state. KRAS G13D is a recognised cycling mutant with NF1 GAP sensitivity, thus upstream co-mutation with NF1 is of importance to evaluate. Methods 471 patients with advanced RAS and/or NF1 mutant NSCLC were retrospectively identified from four tertiary cancer centres using targeted NGS between 2008 �2021. Molecular, clinical and pathological outcome data were collected. Online resources cBioPortal and Project Achilles were used to validate the functional role of findings. Results KRAS mutations were identified in 413 patients (Table). 64 displayed a mutation (mt) in NF1, of which 25 (40%) had a concomitant KRAS mt. Of these double mutants, 12/25 (48%) had a KRAS G12C mt vs. 6/25 (24%) G13D; G13D was significantly more prevalent in double mutants than in NF1 wild type cancers (NF1 WT: 4/281, 1.4%; NF1 mutant: 6/25, 24%; p<0.0001). Although NF1 mutations are expected to be �passengers�, those with a G13D/NF1 co-mutation had a truncating NF1 mt and predicted oncogenic loss of function in 4/5 assessable cases. Functional analysis of NF1 knockdown in KRAS-mutant cell lines demonstrated increased knockdown sensitivity of G13D lung cancer cell lines vs. those harbouring G12C (p=0.04). Wider exploration in cBioPortal demonstrated that G13/NF1 co-mutations occurred in 11 NSCLC patients, of which 82% harboured a G13D mt, and 8 CRC patients: 100% G13D mutant.
CitationAdderley H, Aldea M, Aredo J, Carter M, Church M, Ghaus A, et al. 1787P RAS precision medicine trans-Atlantic partnership: Multi-centre analysis of RAS and NF1 co-mutations in advanced NSCLC. Vol. 32, Annals of Oncology. Elsevier BV; 2021. p. S1221.
JournalAnnals of Oncology