Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 42198-42213 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 26 |
| DOIs | |
| State | Published - Jan 1 2017 |
| Externally published | Yes |
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Keywords
- Comprehensive genomic profiling
- FoundationOne
- Metastatic colorectal cancer
- Next-generation sequencing
- Retrospective
ASJC Scopus subject areas
- Oncology
Cite this
Molecular profiling of metastatic colorectal tumors using nextgeneration sequencing : A single-institution experience. / Gong, Jun; Cho, May; Sy, Marvin; Salgia, Ravi; Fakih, Marwan.
In: Oncotarget, Vol. 8, No. 26, 01.01.2017, p. 42198-42213.Research output: Contribution to journal › Article
}
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
AN - SCOPUS:85021303534
VL - 8
SP - 42198
EP - 42213
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 26
ER -