Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights
Dienstmann, Rodrigo (Vall d'Hebron Institut d'Oncologia)
Elez, Elena (Hospital Universitari Vall d'Hebron)
Argilés Martínez, Guillem (Vall d'Hebron Institut d'Oncologia)
Matos, Ignacio (Vall d'Hebron Institut d'Oncologia)
Sanz García, Enrique (Vall d'Hebron Institut d'Oncologia)
Ortiz, Carolina (Vall d'Hebron Institut d'Oncologia)
Macarulla Mercadé, Teresa (Vall d'Hebron Institut d'Oncologia)
Capdevila Castillón, Jaume (Vall d'Hebron Institut d'Oncologia)
Alsina, Maria (Vall d'Hebron Institut d'Oncologia)
Saurí Nadal, Tamara (Vall d'Hebron Institut d'Oncologia)
Verdaguer, Helena (Vall d'Hebron Institut d'Oncologia)
Vilaró, Marta (Vall d'Hebron Institut d'Oncologia)
Ruiz-Pace, Fiorella (Vall d'Hebron Institut d'Oncologia)
Viaplana, Cristina (Vall d'Hebron Institut d'Oncologia)
García Rodríguez, Ariadna (Vall d'Hebron Institut d'Oncologia)
Landolfi, Stefania (Universitat Autònoma de Barcelona)
Palmer, Héctor G (Vall d'Hebron Institut d'Oncologia)
Nuciforo, Paolo (Vall d'Hebron Institut d'Oncologia)
Rodón Ahnert, Jordi (Vall d'Hebron Institut d'Oncologia)
Vivancos, Ana (Vall d'Hebron Institut d'Oncologia)
Tabernero, Josep (Vall d'Hebron Institut d'Oncologia)

Date:	2017
Abstract:	Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (s, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of s of driver alterations in unpaired primary and metastatic colorectal cancer () at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 samples, 622 had detailed annotation on overall survival in the metastatic setting (met) and 89 received targeted agents matched to ( inhibitors), ( inhibitors), or 3 mutations (3K pathway inhibitors). s of each variant were normalized for tumor purity in the sample (adjs). We found lower adjs for 600E and 3 than for , , and non-V600 variants. 53 and 600E adjs were higher in metastases as compared to primary tumors, and high adjs were found in metastases of patients with wild-type primary tumors previously exposed to antibodies. Patients with - or 600E -mutated tumors, irrespective of adjs, had worse met. There was no significant association between adjs and time to progression on targeted therapies matched to , , or 3 mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4. 5%). In conclusion, the lower 600E and 3 adjs in subsets of primary tumors indicate subclonality of these driver genes. Differences in adjs between metastases and primary tumors suggest that approved therapies may result in selection of 600E - and -resistant clones and an increase in genomic heterogeneity with acquired 53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.
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:	Clonality ; Colorectal cancer ; Driver gene ; Mutant allele fraction
Published in:	Molecular Oncology, Vol. 11, Issue 9 (September 2017) , p. 1263-1272, ISSN 1878-0261

DOI: 10.1002/1878-0261.12099
PMID: 28618197

10 p, 506.2 KB

The record appears in these collections:
Articles > Research articles
Articles > Published articles