Atypical RAS mutations in metastatic colorectal cancer Journal Article


Authors: Pietrantonio, F.; Yaeger, R.; Schrock, A. B.; Randon, G.; Romero-Cordoba, S.; Rossini, D.; Fucà, G.; Ross, J. S.; Kotani, D.; Madison, R.; Kim, S. T.; Salvatore, L.; Raimondi, A.; Pagani, F.; Borelli, B.; Perrone, F.; Di Bartolomeo, M.; Miller, V. A.; Ali, S. M.; Lee, J.; Yoshino, T.; De Braud, F.; Falcone, A.; Hechtman, J. F.; Cremolini, C.
Article Title: Atypical RAS mutations in metastatic colorectal cancer
Abstract: PURPOSE To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At-RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. MATERIALS AND METHODS By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At-RAS mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At-RAS-positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS At-RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At-RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS/BRAF V600E mutations and NF1 mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At-RAS, typical RAS, or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (P , .001). No significant OS difference (P = .240) was found between patients with At- RAS versus typical RAS-mutated mCRC. Only one of six patients evaluable for primary resistance to anti- epidermal growth factor receptors achieved tumor response. CONCLUSION At-RAS mutations may be a marker for RAS pathway activation and can be associated with high cooccurrence of POLE exonuclease domain mutations. © 2019 by American Society of Clinical Oncology.
Keywords: adult; controlled study; treatment response; aged; gene mutation; major clinical study; overall survival; wild type; cancer resistance; panitumumab; microsatellite instability; neurofibromin; ras protein; codon; b raf kinase; metastatic colorectal cancer; high throughput sequencing; human; male; female; priority journal; article; median survival time
Journal Title: JCO Precision Oncology
Volume: 3
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2019-09-17
Language: English
DOI: 10.1200/po.19.00136
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
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MSK Authors
  1. Rona Denit Yaeger
    124 Yaeger
  2. Jaclyn Frances Hechtman
    164 Hechtman