Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy.
Journal: 2019/October - Theranostics
ISSN: 1838-7640
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.
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Theranostics 9(23): 6856-6866

Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy

+7 authors

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Supplementary tables.

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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
Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Center for Bioinformatics, Peking University, Beijing, China
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
Department of Pathology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
✉ Corresponding author: W.T. (nc.ca.smacic@newnat) or D.L. (nc.ca.smacic@xdnil)
# These authors contributed equally to this work.
Competing Interests: The authors have declared that no competing interest exists.
Competing Interests: The authors have declared that no competing interest exists.
Received 2019 Jun 21; Accepted 2019 Jul 29.
This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

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
Abstract

Acknowledgments

This research was supported by the National Key Basic Research and Development Program of China (973 project, grant no. 2014CB542004 to Wen Tan) and Chinese Academy Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (grant no. 2016-I2M-1-001 and 2019-I2M-1-003 to Wen Tan).

Contributions

D.L. and W.T. conceptualized and supervised this study, J.Y. and Y.H. contributed to the study design. J.Y., Y. Lin, X.Z., Z.Z. and G.G. contributed to bioinformatics and statistical analysis. J.J., S.Z., H.L., T.F., J.C., J.Z., C.W. and Y. Li responded to patient recruitment and or biospecimen and clinical data collection. Y. Lin, D.L., J.Y. and W.T. prepared manuscript. All authors have reviewed and approved the manuscript. We acknowledge the Novogene Bioinformatics Technology Co. for assistance in DNA sequencing.

Acknowledgments

Abbreviations

CCFcancer cell fraction
COSMICcatalogue of somatic mutation in cancer
CNVscopy number variations
CRCcolorectal cancer
CRTchemoradiotherapy
FFPEformalin-fixed paraffin-embedded
KPSKarnofsky performance score
NMFnon-negative matrix factorization
ROCreceiver operating characteristic
SNVssingle nucleotide variants
TCGAthe cancer genome atlas
TRGtumor regression grade
VAFsvariant allele frequencies
WESwhole-exome sequencing
Abbreviations
Click here for additional data file.(2.0M, pdf)Click here for additional data file.(8.4M, xlsx)

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