Clinical and Functional Characterization of Atypical KRAS / NRAS Mutations in Metastatic Colorectal Cancer

Mutations in ( ) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characteriz...

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Bibliographic Details
Published in:Clinical cancer research 2021-08, Vol.27 (16), p.4587-4598
Main Authors: Loree, Jonathan M, Wang, Yucai, Syed, Muddassir A, Sorokin, Alexey V, Coker, Oluwadara, Xiu, Joanne, Weinberg, Benjamin A, Vanderwalde, Ari M, Tesfaye, Anteneh, Raymond, Victoria M, Miron, Benjamin, Tarcic, Gabi, Zelichov, Ori, Broaddus, Russell R, Ng, Patrick Kwok Shing, Jeong, Kang Jin, Tsang, Yiu Huen, Mills, Gordon B, Overman, Michael J, Grothey, Axel, Marshall, John L, Kopetz, Scott
Format: Article
Language:English
Subjects:
Aged
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Female
GTP Phosphohydrolases - genetics
Humans
Male
Membrane Proteins - genetics
Middle Aged
Mutation
Neoplasm Metastasis
Proto-Oncogene Proteins p21(ras) - genetics
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Summary:Mutations in ( ) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical variants. Using an cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. exon 2, extended , and atypical mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no codon 117/146 and only one codon 59 mutation was noted. Atypical mutations had worse overall survival than wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; = 0.014). We functionally characterized 114 variants with the FACT assay. All exon 2 and extended mutations appeared activating. Of 57 atypical variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. We provide best available evidence to guide treatment when atypical variants are identified. L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included variants and functionally relevant.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-21-0180