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Genomic and transcriptomic characterisation of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.pdf (1.64 MB)

Genomic and transcriptomic characterisation of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

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posted on 2024-05-30, 16:08 authored by Sinead ToomeySinead Toomey, Jillian R. Gunther, Aoife Carr, David C. Weksberg, Valentina Thomas, Manuela Salvucci, Orna Bacon, Sherif El-MasrySherif El-Masry, Joanna FayJoanna Fay, Elaine KayElaine Kay, Katherine SheehanKatherine Sheehan, Deborah McNamaraDeborah McNamara, Keith L Sanders, Geena Mathew, Oscar BreathnachOscar Breathnach, Liam GroganLiam Grogan, Patrick MorrisPatrick Morris, Wai C Foo, Yi-Qian N You, Jochen PrehnJochen Prehn, Brian O'Neill, Sunil Krishnan, Bryan HennessyBryan Hennessy, Simon FurneySimon Furney
Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre-or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.

Funding

North East Cancer Research and Education Trust (NECRET)

Science Foundation Ireland investigator award 13/IA/1881

St. Luke’s Institute of Cancer Research

Fox and Kerins families

European Commission (FP7-PEOPLE-2013-IEF—6270270)

Royal College of Surgeons in Ireland StAR programme

SRC MTC: Molecular Therapeutics for Cancer: Translational Research to Individualise Therapy with Target Agents

Science Foundation Ireland

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History

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data will be available on request upon publication from the European Genome-phenome Archive (EGA) database by contacting the data access committee (Genomic Oncology Research Group DAC: EGAC00001001585) assigned for this project

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Toomey S. et al. Genomic and transcriptomic characterisation of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Cancers (Basel). 2020;12(7):1808.

Publication Date

6 July 2020

PubMed ID

32640573

Department/Unit

  • Beaumont Hospital
  • Centre for Systems Medicine
  • Medicine
  • Molecular Medicine
  • Pathology
  • Physiology and Medical Physics
  • Surgery

Research Area

  • Neurological and Psychiatric Disorders
  • Cancer

Publisher

MDPI

Version

  • Published Version (Version of Record)