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Theranostics 2019; 9(23):6856-6866. doi:10.7150/thno.37794 This issue Cite

Research Paper

Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy

Jie Yang^1,#, Yuan Lin^2,3,#, Ying Huang¹, Jing Jin⁴, Shuangmei Zou⁵, Xiaolong Zhang⁶, Hongmin Li¹, Ting Feng¹, Jinna Chen¹, Zhixiang Zuo⁶, Jian Zheng⁶, Yexiong Li⁴, Ge Gao^2,3, Chen Wu¹, Wen Tan^1✉, Dongxin Lin^1,6✉

1. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2. Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China
3. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Center for Bioinformatics, Peking University, Beijing, China
4. Department of Radiation Oncology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
5. Department of Pathology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
6. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
# These authors contributed equally to this work.

✉ Corresponding author: W.T. (tanwenac.cn) or D.L. (lindxac.cn)

Abstract

Resistance to preoperative chemoradiotherapy (CRT) is a major obstacle to cancer treatment in patients with locally advanced rectal cancer. This study was to explore genome alterations in rectal cancer under CRT stress.

Methods: Whole-exome sequencing (WES) was performed on 28 paired tumors collected before and after CRT from the same patients who did not respond to CRT treatment. Somatic point mutations and copy number variations were detected by VarScan2 and Exome CNVs respectively using paired tumor and blood samples. Somatic alterations associated with CRT resistance were inferred considering differences in significantly mutated genes, mutation counts and cancer cell fraction between matched pre- and post-CRT tumors. We employed SignatureAnalyzer to infer mutation signatures and PyClone to decipher clonal evolution and examine intratumoral heterogeneity in tumors before and after CRT. The associations between intratumoral heterogeneity and patients' survival were analyzed using the log-rank test and the Cox regression model.

Results: (i) Recurrent mutations in CTDSP2, APC, KRAS, TP53 and NFKBIZ confer selective advantages on cancer cells and made them resistant to CRT treatment. (ii) CRT alters the genomic characteristics of tumors at both the somatic mutation and the copy number variation levels. (iii) CRT-resistant tumors exhibit either a branched or a linear evolution pattern. (iv) Different recurrent mutation signatures in pre-CRT and post-CRT patients implicate mutational processes underlying the evolution of CRT-resistant tumors. (v) High intratumoral heterogeneity in pre- or post-CRT is associated with poor patients' survival.

Conclusion: Our study reveals genome landscapes in rectal cancer before and after CRT and tumors evolution under CRT stress. The treatment-associated characteristics are useful for further investigations of CRT resistance in rectal cancer.

Keywords: whole-exome sequencing, mutation, copy-number variation, survival, rectal cancer

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