title: Chemoradiation provides a physiological selective pressure that increases the expansion of aberrant TP53 tumor variants in residual rectal cancerous regions.
abstract: Neoadjuvant chemoradiotherapy has been introduced in patients with surgically resected rectal cancer and reduced the local recurrence. Heterogeneity exists in rectal cancer, and we hypothesized that there are subclones resistant to chemoradiotherapy within the cancer mass. We performed DNA-targeted sequencing of pre- and post-treatment tumor tissues obtained from 20 rectal cancer patients who received chemoradiotherapy. The variant frequency of the mutant clones was compared between pre- and post-treatment samples of nine non-responder patients. RNA-targeted sequencing of 57 genes related to sensitivity to chemotherapy and radiotherapy was performed for the paired samples. Immunohistochemical analyses of p53 expression were also performed on the paired samples from the nine non-responder patients. DNA-sequencing detected frequent mutations of suppressor genes including TP53, APC and FBXW7 in the post-treatment samples of the nine non-responders. The frequency of TP53 mutations showed significant increases after chemoradiotherapy. RNA-targeted sequencing of 29 tumor tissues demonstrated that decreased expression of three genes and increased expression of four genes were detected in the post-treatment samples. Significantly increased expression of TP53 was observed in the post-treatment samples. Immunohistochemical staining for p53 revealed that increased p53 intensity scores were observed after chemoradiotherapy. These results suggest that the tumors with TP53 mutations tend to accumulate through chemoradiotherapy.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kazama
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Nagai
authors.forename: Koji
authors.initials: K
authors.lastname: Murono
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ishihara
authors.forename: Eiji
authors.initials: E
authors.lastname: Sunami
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059186:Chemoradiotherapy, Adjuvant; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D009154:Mutation; D020360:Neoadjuvant Therapy; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D005641:Tegafur / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014498:Uracil / Q000008:administration & dosage
chemical_list: D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005641:Tegafur; D014498:Uracil; D002955:Leucovorin