Atypical RAS Mutations in Metastatic Colorectal Cancer

Abstract

Background. 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. Methods. By exploiting five next-generation sequencing sources [Italian collaboration (i), Memorial Sloan-Kettering Cancer Center (ii), Samsung Medical Center (iii), BREAC Japanese study (iv) and Foundation Medicine (v)] we retrieved 175 At-RAS mutated cases. Molecular data were obtained from 163 samples from sources (ii) and (v). Clinical data were available for 27 At-RAS positive and 467 negative cases from sources (i-iv). Findings. At-RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable MSI status, 11 (8%) were MSI-high. POLE exonuclease domain mutations had dramatically higher frequency (8%) than expected and were found only in MSS tumors with high tumor mutational burden (TMB). Overall, 17% (28/163) of At-RAS cases had TMB >10 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). RAS/BRAF wild-type mCRC patients 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<0*001). No significant OS difference (P=0*240) was found between At-RAS versus typical RAS mutated mCRC patients. Only 1/6 patients evaluable for primary resistance to anti-EGFRs achieved tumor response. Interpretation. At-RAS mutations may be a marker for RAS pathway activation and can be associated with TMB-high status in MSS tumors. Funding. None. Declaration of Interest: The authors have declared no conflicts of interest. Ethical Approval: The study was approved by the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Institutional Review Board (study ID: INT 117/15) and conducted according to the ethical principles for medical research involving human subjects adopted in the Declaration of Helsinki. All alive patients signed a written informed consent.