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. 2021 Apr;15(4):901-914.
doi: 10.1002/1878-0261.12907. Epub 2021 Feb 23.

Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies

Leonie K de Klerk #  1   2   3 , Ruben S A Goedegebuure #  1   3 , Nicole C T van Grieken  4 , Johanna W van Sandick  5 , Annemieke Cats  6 , Jurrien Stiekema  5 , Rosa T van der Kaaij  5 , Arantza Farina Sarasqueta  4   7 , Manon van Engeland  8 , Maarten A J M Jacobs  9 , Roy L J van Wanrooij  9 , Donald L van der Peet  10 , Aaron R Thorner  11 , Henk M W Verheul  1 , Victor L J L Thijssen  12 , Adam J Bass #  2   13 , Sarah Derks #  1   3
Affiliations

Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies

Leonie K de Klerk et al. Mol Oncol. 2021 Apr.

Abstract

Identification of molecular predictive markers of response to neoadjuvant chemoradiation could aid clinical decision-making in patients with localized oesophageal cancer. Therefore, we subjected pretreatment biopsies of 75 adenocarcinoma (OAC) and 16 squamous cell carcinoma (OSCC) patients to targeted next-generation DNA sequencing, as well as biopsies of 85 OAC and 20 OSCC patients to promoter methylation analysis of eight GI-specific genes, and subsequently searched for associations with histopathological response and disease-free (DFS) and overall survival (OS). Thereby, we found that in OAC, CSMD1 deletion (8%) and ETV4 amplification (5%) were associated with a favourable histopathological response, whereas SMURF1 amplification (5%) and SMARCA4 mutation (7%) were associated with an unfavourable histopathological response. KRAS (15%) and GATA4 (7%) amplification were associated with shorter OS. In OSCC, TP63 amplification (25%) and TFPI2 (10%) gene promoter methylation were associated with an unfavourable histopathological response and shorter DFS (TP63) and OS (TFPI2), whereas CDKN2A deletion (38%) was associated with prolonged OS. In conclusion, this study identified candidate genetic biomarkers associated with response to neoadjuvant chemoradiotherapy in patients with localized oesophageal cancer.

Keywords: DNA sequencing; chemoradiation; gene methylation; genetic biomarkers; oesophageal cancer; predictive markers.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Overview of genomic alterations in relation to histopathological response according to Mandard's tumour regression grade to neoadjuvant chemoradiotherapy in patients with oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC). Percentages indicate frequency of occurrence within OAC and OSCC, respectively.
Fig. 2
Fig. 2
(Epi)genetic alterations in relation to histopathological response to neoadjuvant chemoradiotherapy in patients with oesophageal cancer. (A, B) Associations between (epi)genetic alterations and histopathological response in oesophageal adenocarcinoma (OAC). (A) CSMD1 deletion and ETV4 amplification were associated with a favourable tumour regression grade (TRG), whereas SMURF1 amplification was associated with an unfavourable TRG in OAC. (B) SMURF1 amplification and SMARCA4 mutation were associated with an unfavourable prognostic score (PRSC) in OAC. (C, D) Associations between (epi)genetic alterations and histopathological response in oesophageal squamous cell carcinoma (OSCC). (C) TP63 and BCL6 amplification (both on chromosomal region 3q27.3‐28) were associated with an unfavourable TRG in OSCC. (D) TFPI2 promoter methylation was associated with an unfavourable PRSC in OSCC. Linear‐by‐linear, exact test.
Fig. 3
Fig. 3
(Epi)genetic alterations in relation to survival in patients with (A) oesophageal adenocarcinoma (OAC) and (B, C) oesophageal squamous cell carcinoma (OSCC). (A) GATA4 and KRAS amplification was associated with a shorter overall survival (OS) in patients with OAC. (B) In patients with OSCC, TP63 amplification was associated with a shorter OS, whereas deletion of CDKN2A was associated with a longer OS. (C) Patients with OSCC and TFPI2 promoter methylation had a shorter OS. Log‐rank test.
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