Molecular profiling of metastatic colorectal tumors using nextgeneration sequencing

TY - JOUR

T1 - Molecular profiling of metastatic colorectal tumors using nextgeneration sequencing

T2 - A single-institution experience

AU - Gong, Jun

AU - Cho, May

AU - Sy, Marvin

AU - Salgia, Ravi

AU - Fakih, Marwan

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC). Methods: We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using nextgeneration sequencing (NGS) via FoundationOne. Results: Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation. Conclusions: Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.

AB - Background: Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC). Methods: We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using nextgeneration sequencing (NGS) via FoundationOne. Results: Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation. Conclusions: Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.

KW - Comprehensive genomic profiling

KW - FoundationOne

KW - Metastatic colorectal cancer

KW - Next-generation sequencing

KW - Retrospective

UR - http://www.scopus.com/inward/record.url?scp=85021303534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021303534&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.15030

DO - 10.18632/oncotarget.15030

M3 - Article

VL - 8

SP - 42198

EP - 42213

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 26

ER -