Molecular profiling of metastatic colorectal tumors using nextgeneration sequencing

A single-institution experience

Jun Gong, May Cho, Marvin Sy, Ravi Salgia, Marwan Fakih

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)42198-42213
Number of pages16
JournalOncotarget
Volume8
Issue number26
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Colorectal Neoplasms
Mutation
Neoplasms
Tumor Burden
Colon
Retrospective Studies
Phenotype
Therapeutics

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 journalArticle

Gong, Jun ; Cho, May ; Sy, Marvin ; Salgia, Ravi ; Fakih, Marwan. / Molecular profiling of metastatic colorectal tumors using nextgeneration sequencing : A single-institution experience. In: Oncotarget. 2017 ; Vol. 8, No. 26. pp. 42198-42213.
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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.",
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