TY - JOUR
T1 - Genomic and transcriptomic characterisation of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer
AU - Toomey, Sinead
AU - Gunther, Jillian
AU - Carr, Aoife
AU - Weksberg, David C.
AU - Thomas, Valentina
AU - Salvucci, Manuela
AU - Bacon, Orna
AU - Sherif, El Masry
AU - Fay, Joanna
AU - Kay, Elaine W.
AU - Sheehan, Katherine M.
AU - McNamara, Deborah A.
AU - Sanders, Keith L.
AU - Mathew, Geena
AU - Breathnach, Oscar S.
AU - Grogan, Liam
AU - Morris, Patrick G.
AU - Foo, Wai C.
AU - You, Yi Qian N.
AU - Prehn, Jochen H.
AU - O’neill, Brian
AU - Krishnan, Sunil
AU - Hennessy, Bryan T.
AU - Furney, Simon J.
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Locally advanced rectal cancer
KW - Microbiome
KW - Microsatellite instability
KW - Neoadjuvant chemoradiotherapy
KW - RNA-seq
KW - Whole exome sequencing
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U2 - 10.3390/cancers12071808
DO - 10.3390/cancers12071808
M3 - Article
C2 - 32640573
AN - SCOPUS:85088778944
SN - 2072-6694
VL - 12
SP - 1
EP - 16
JO - Cancers
JF - Cancers
IS - 7
M1 - 1808
ER -