AUTHOR=Takenaka Isabella Kuniko T. M. , Bartelli Thais F. , Defelicibus Alexandre , Sendoya Juan M. , Golubicki Mariano , Robbio Juan , Serpa Marianna S. , Branco Gabriela P. , Santos Luana B. C. , Claro Laura C. L. , dos Santos Gabriel Oliveira  , Kupper Bruna E. C. , da Silva Israel T. , Llera Andrea S. , de Mello Celso A. L. , Riechelmann Rachel P. , Dias-Neto Emmanuel , Iseas Soledad , Aguiar Samuel , Nunes Diana Noronha 

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

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.809441

DOI=10.3389/fonc.2022.809441

ISSN=2234-943X

ABSTRACT=<p>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, <italic>n</italic> = 17; non-responders, <italic>n</italic> = 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 (<italic>p</italic> = 0.0021), as well as the co-occurrence of <italic>APC</italic> and <italic>FAT4</italic> mutations (<italic>p</italic> &lt; 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 <italic>Hungatella, Flavonifractor</italic>, and <italic>Methanosphaera</italic> (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of <italic>Enhydrobacter, Paraprevotella</italic> (LDA score ≥3) and <italic>Finegoldia</italic> (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.</p>