Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients
Riera, Pau (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Rodríguez-Santiago, Benjamín (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Lasa, Adriana (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Gonzalez-Quereda, L. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Martín, Berta (Institut d'Investigació Biomèdica Sant Pau)
Salazar, Juliana (Institut d'Investigació Biomèdica Sant Pau)
Sebio, Ana (Institut d'Investigació Biomèdica Sant Pau)
Virgili, Anna C. (Institut d'Investigació Biomèdica Sant Pau)
Minguillón Pedreño, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Camps-Fajol, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Páez, David (Institut d'Investigació Biomèdica Sant Pau)

Date:	2020
Abstract:	Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.
Grants:	Instituto de Salud Carlos III CM18/00207
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Genetic variants ; Predictive biomarkers ; Anti-egfr monoclonal antibodies ; Colorectal cancer ; Case-control study
Published in:	Cancers, Vol. 12, Num. 8 (August 2020) , art. 2245, ISSN 2072-6694

DOI: 10.3390/cancers12082245
PMID: 32796636

15 p, 691.2 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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