Exome and Tissue-Associated Microbiota as Predictive Markers of Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer

Frontiers in Oncology

Emmanuel Dias-Neto¹  Diana Noronha Nunes²  Mariano Golubicki³  Juan Robbio³  Samuel Aguiar⁴  Bruna E. C. Kupper⁴  Rachel P. Riechelmann⁵  Celso A. L. de Mello⁵  Gabriel Oliveirados Santos⁶  Laura C. L. Claro⁶  Juan M. Sendoya⁷  Andrea S. Llera⁷  Alexandre Defelicibus⁹  Israel T. da Silva⁹  Gabriela P. Branco^1,10  Luana B. C. Santos^1,10  Marianna S. Serpa^1,10  Isabella Kuniko T. M. Takenaka^1,10  Thais F. Bartelli^1,10  Soledad Iseas^1,11 

[1] 0Laboratory of Neurosciences (LIM-27) Alzira Denise Hertzog Silva, Institute of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil;1National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO), São Paulo, Brazil;Clinical Oncology, Intergrupo Argentino para el Tratamiento de los Tumores Gastrointestinales (IATTGI), Buenos Aires, Argentina;Colorectal Cancer Department, A.C.Camargo Cancer Center, São Paulo, Brazil;Department of Clinical Oncology, A.C.Camargo Cancer Center, São Paulo, Brazil;Department of Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil;Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina;Laboratorio de Terapia Molecular y Celular – Genomics Unit, Fundación Instituto Leloir, Buenos Aires, Argentina;Laboratory of Bioinformatics and Computational Biology, International Center for Research, A.C. Camargo Cancer Center, São Paulo, Brazil;Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil;Oncology Unit, Hospital de Gastroenterología Carlos Bonorino Udaondo, Buenos Aires, Argentina;

关键词: locally advanced rectal cancer;    neoadjuvant chemoradiotherapy;    whole exome sequencing;    microbiota;    biomarkers of treatment response;    mutational signatures;   

DOI  :  10.3389/fonc.2022.809441

来源: DOAJ

【 摘 要 】

The clinical and pathological responses to multimodal neoadjuvant therapy in locally advanced rectal cancers (LARCs) remain unpredictable, and robust biomarkers are still lacking. Recent studies have shown that tumors present somatic molecular alterations related to better treatment response, and it is also clear that tumor-associated bacteria are modulators of chemotherapy and immunotherapy efficacy, therefore having implications for long-term survivorship and a good potential as the biomarkers of outcome. Here, we performed whole exome sequencing and 16S ribosomal RNA (rRNA) amplicon sequencing from 44 pre-treatment LARC biopsies from Argentinian and Brazilian patients, treated with neoadjuvant chemoradiotherapy or total neoadjuvant treatment, searching for predictive biomarkers of response (responders, n = 17; non-responders, n = 27). In general, the somatic landscape of LARC was not capable to predict a response; however, a significant enrichment in mutational signature SBS5 was observed in non-responders (p = 0.0021), as well as the co-occurrence of APC and FAT4 mutations (p < 0.05). Microbiota studies revealed a similar alpha and beta diversity of bacteria between response groups. Yet, the linear discriminant analysis (LDA) of effect size indicated an enrichment of Hungatella, Flavonifractor, and Methanosphaera (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of Enhydrobacter, Paraprevotella (LDA score ≥3) and Finegoldia (LDA score ≥4). Altogether, the evaluation of these biomarkers in pre-treatment biopsies could eventually predict a neoadjuvant treatment response, while in post-treatment samples, it could help in guiding non-operative treatment strategies.

【 授权许可】

Unknown