Open AccessAnalysis of mutant allele fractions in driver genes in colorectal cancer – biological and clinical insights
Author(s) -
Dienstmann Rodrigo,
Elez Elena,
Argiles Guillem,
Matos Ignacio,
SanzGarcia Enrique,
Ortiz Carolina,
Macarulla Teresa,
Capdevila Jaume,
Alsina Maria,
Sauri Tamara,
Verdaguer Helena,
Vilaro Marta,
RuizPace Fiorella,
Viaplana Cristina,
Garcia Ariadna,
Landolfi Stefania,
Palmer Hector G.,
Nuciforo Paolo,
Rodon Jordi,
Vivancos Ana,
Tabernero Josep
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12099
Subject(s) - kras , neuroblastoma ras viral oncogene homolog , colorectal cancer , cancer research , allele , medicine , cancer , oncology , gene , biology , genetics
Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions ( MAF 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 MAF s of driver alterations in unpaired primary and metastatic colorectal cancer ( CRC ) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting ( OS met) and 89 received targeted agents matched to KRAS ( MEK inhibitors), BRAF ( BRAF inhibitors), or PIK 3 CA mutations ( PI 3K pathway inhibitors). MAF s of each variant were normalized for tumor purity in the sample (adj MAF s). We found lower adj MAF s for BRAF V 600E and PIK 3 CA than for KRAS , NRAS , and BRAF non‐V600 variants. TP 53 and BRAF V 600E adj MAF s were higher in metastases as compared to primary tumors, and high KRAS adj MAF s were found in CRC metastases of patients with KRAS wild‐type primary tumors previously exposed to EGFR antibodies. Patients with RAS ‐ or BRAF V 600E ‐mutated tumors, irrespective of adj MAF s, had worse OS met. There was no significant association between adj MAF s and time to progression on targeted therapies matched to KRAS , BRAF , or PIK 3 CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAF V 600E and PIK 3 CA adj MAF s in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adj MAF s between metastases and primary tumors suggest that approved therapies may result in selection of BRAF V 600E ‐ and KRAS ‐resistant clones and an increase in genomic heterogeneity with acquired TP 53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adj MAF s levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.