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.