TY - JOUR
T1 - Genotyping of circulating tumor DNA reveals the clinically actionable mutation landscape of advanced colorectal cancer
AU - Cao, Weiguo
AU - Xu, Yaping
AU - Chang, Lianpeng
AU - Gong, Yuhua
AU - Li, Liren
AU - Mo, Xianwei
AU - Zhang, Xin
AU - Lin, Guole
AU - Zhou, Jiaolin
AU - Liu, Dan
AU - Yi, Yuting
AU - Dai, Pingping
AU - Zhu, Chenchen
AU - Liu, Tao
AU - Chu, Yuxing
AU - Guan, Yanfang
AU - Chen, Yongsheng
AU - Wang, Jiayin
AU - Xia, Xuefeng
AU - Yang, Ling
AU - Yi, Xin
AU - Cheng, Yong
N1 - Publisher Copyright:
2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Circulating tumor DNA (ctDNA) enables genomic profiling of colorectal cancer. We investigated therapeutic targets by performing ctDNA panel-captured sequencing of 152 blood samples from advanced stage patients, from which somatic mutations and potentially actionable targets were evaluated. An additional 11 matched tissue samples were retrospectively obtained to verify target validity. The mutation frequencies of 1,127 collective genetic variants identified in our study strongly correlated with those of multiple public databases (Pearson R2 ¼ 0.92, P < 0.0001). The clonal fraction of driver genes was 90.3%, which was significantly higher than that of potential passenger genes (58.12%). Totally, 90 drug-sensitive genes from 56 patients (36.84%) were identified, including recurring targets PIK3CA, FBXW7, EGFR, BRAF, and NRAS. Various resistance mechanisms of anti-EGFR antibodies were revealed via ctDNA profiling, with 29 patients individually exhibiting multiple mechanisms, suggesting considerable resistance heterogeneity in our study population. Of the matched tissue/ blood pairs, 88.14% of tissue-derived mutations were detected in ctDNA, and 88.9% of actionable targets were validated. The mutational landscape of ctDNA was highly consistent with tissue databases, and ctDNA profiling showed favorable concordance with tumor tissues in our matched analysis. Thus, comprehensive ctDNA genotyping is a promising noninvasive alternative to biopsy-derived analysis for determining targeted therapy in advanced colorectal cancer.
AB - Circulating tumor DNA (ctDNA) enables genomic profiling of colorectal cancer. We investigated therapeutic targets by performing ctDNA panel-captured sequencing of 152 blood samples from advanced stage patients, from which somatic mutations and potentially actionable targets were evaluated. An additional 11 matched tissue samples were retrospectively obtained to verify target validity. The mutation frequencies of 1,127 collective genetic variants identified in our study strongly correlated with those of multiple public databases (Pearson R2 ¼ 0.92, P < 0.0001). The clonal fraction of driver genes was 90.3%, which was significantly higher than that of potential passenger genes (58.12%). Totally, 90 drug-sensitive genes from 56 patients (36.84%) were identified, including recurring targets PIK3CA, FBXW7, EGFR, BRAF, and NRAS. Various resistance mechanisms of anti-EGFR antibodies were revealed via ctDNA profiling, with 29 patients individually exhibiting multiple mechanisms, suggesting considerable resistance heterogeneity in our study population. Of the matched tissue/ blood pairs, 88.14% of tissue-derived mutations were detected in ctDNA, and 88.9% of actionable targets were validated. The mutational landscape of ctDNA was highly consistent with tissue databases, and ctDNA profiling showed favorable concordance with tumor tissues in our matched analysis. Thus, comprehensive ctDNA genotyping is a promising noninvasive alternative to biopsy-derived analysis for determining targeted therapy in advanced colorectal cancer.
UR - https://www.scopus.com/pages/publications/85067214667
U2 - 10.1158/1535-7163.MCT-18-1247
DO - 10.1158/1535-7163.MCT-18-1247
M3 - 文章
C2 - 31015309
AN - SCOPUS:85067214667
SN - 1535-7163
VL - 18
SP - 1158
EP - 1167
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -
可持续发展目标 3 良好健康与福祉