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

L.K. de Klerk; R.S.A. Goedegebuure; N.C.T. van Grieken; J.W. van Sandick; A. Cats; J. Stiekema; R.T. van der Kaaij; A.F. Sarasqueta; M. van Engeland; M.A.J.M. Jacobs; R.L.J. van Wanrooij; D.L. van der Peet; A.R. Thorner; H.M.W. Verheul; V.L.J.L. Thijssen; A.J. Bass; S. Derks

doi:10.1002/1878-0261.12907

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

L.K. de Klerk, R.S.A. Goedegebuure, N.C.T. van Grieken, J.W. van Sandick, A. Cats, J. Stiekema, R.T. van der Kaaij, A.F. Sarasqueta, M. van Engeland, M.A.J.M. Jacobs, R.L.J. van Wanrooij, D.L. van der Peet, A.R. Thorner, H.M.W. Verheul, V.L.J.L. Thijssen, A.J. Bass^*, S. Derks^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	901-914
Number of pages	14
Journal	Molecular oncology
Volume	15
Issue number	4
DOIs	https://doi.org/10.1002/1878-0261.12907
Publication status	Published - Apr 2021

Keywords

chemoradiation
dna sequencing
gene methylation
genetic biomarkers
oesophageal cancer
predictive markers
COMPLEX
PROTEIN
PROGNOSIS
ADENOCARCINOMA
PREOPERATIVE CHEMORADIOTHERAPY
CHEMOTHERAPY
HETEROGENEITY
RESISTANCE
CSMD1
PROGRESSION
DNA sequencing

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de Klerk, L. K., Goedegebuure, R. S. A., van Grieken, N. C. T., van Sandick, J. W., Cats, A., Stiekema, J., van der Kaaij, R. T., Sarasqueta, A. F., van Engeland, M., Jacobs, M. A. J. M., van Wanrooij, R. L. J., van der Peet, D. L., Thorner, A. R., Verheul, H. M. W., Thijssen, V. L. J. L., Bass, A. J., & Derks, S. (2021). Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies. Molecular oncology, 15(4), 901-914. https://doi.org/10.1002/1878-0261.12907

@article{83e1890a52fa4462b6d62089e87d7679,

title = "Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies",

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 = "chemoradiation, dna sequencing, gene methylation, genetic biomarkers, oesophageal cancer, predictive markers, COMPLEX, PROTEIN, PROGNOSIS, ADENOCARCINOMA, PREOPERATIVE CHEMORADIOTHERAPY, CHEMOTHERAPY, HETEROGENEITY, RESISTANCE, CSMD1, PROGRESSION, DNA sequencing",

author = "{de Klerk}, L.K. and R.S.A. Goedegebuure and {van Grieken}, N.C.T. and {van Sandick}, J.W. and A. Cats and J. Stiekema and {van der Kaaij}, R.T. and A.F. Sarasqueta and {van Engeland}, M. and M.A.J.M. Jacobs and {van Wanrooij}, R.L.J. and {van der Peet}, D.L. and A.R. Thorner and H.M.W. Verheul and V.L.J.L. Thijssen and A.J. Bass and S. Derks",

note = "Funding Information: We thank the Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA) for their assistance in searching pretreatment biopsy specimen from the referring hospitals. SD is supported by the Dutch Cancer Society (VU2012‐5351), the Netherlands Organization for Scientific Research (NOW, 016.186.022), American Society of Clinical Oncology (YIA 2016) and Oncode Institute. AB receives funding from Bayer, Merck and Novartis. Funding Information: We thank the Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA) for their assistance in searching pretreatment biopsy specimen from the referring hospitals. SD is supported by the Dutch Cancer Society (VU2012-5351), the Netherlands Organization for Scientific Research (NOW, 016.186.022), American Society of Clinical Oncology (YIA 2016) and Oncode Institute. AB receives funding from Bayer, Merck and Novartis. Publisher Copyright: {\textcopyright} 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2021",

month = apr,

doi = "10.1002/1878-0261.12907",

language = "English",

volume = "15",

pages = "901--914",

journal = "Molecular oncology",

issn = "1574-7891",

publisher = "John Wiley & Sons Inc.",

number = "4",

}

de Klerk, LK, Goedegebuure, RSA, van Grieken, NCT, van Sandick, JW, Cats, A, Stiekema, J, van der Kaaij, RT, Sarasqueta, AF, van Engeland, M, Jacobs, MAJM, van Wanrooij, RLJ, van der Peet, DL, Thorner, AR, Verheul, HMW, Thijssen, VLJL, Bass, AJ & Derks, S 2021, 'Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies', Molecular oncology, vol. 15, no. 4, pp. 901-914. https://doi.org/10.1002/1878-0261.12907

TY - JOUR

T1 - Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies

AU - de Klerk, L.K.

AU - Goedegebuure, R.S.A.

AU - van Grieken, N.C.T.

AU - van Sandick, J.W.

AU - Cats, A.

AU - Stiekema, J.

AU - van der Kaaij, R.T.

AU - Sarasqueta, A.F.

AU - van Engeland, M.

AU - Jacobs, M.A.J.M.

AU - van Wanrooij, R.L.J.

AU - van der Peet, D.L.

AU - Thorner, A.R.

AU - Verheul, H.M.W.

AU - Thijssen, V.L.J.L.

AU - Bass, A.J.

AU - Derks, S.

N1 - Funding Information: We thank the Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA) for their assistance in searching pretreatment biopsy specimen from the referring hospitals. SD is supported by the Dutch Cancer Society (VU2012‐5351), the Netherlands Organization for Scientific Research (NOW, 016.186.022), American Society of Clinical Oncology (YIA 2016) and Oncode Institute. AB receives funding from Bayer, Merck and Novartis. Funding Information: We thank the Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA) for their assistance in searching pretreatment biopsy specimen from the referring hospitals. SD is supported by the Dutch Cancer Society (VU2012-5351), the Netherlands Organization for Scientific Research (NOW, 016.186.022), American Society of Clinical Oncology (YIA 2016) and Oncode Institute. AB receives funding from Bayer, Merck and Novartis. Publisher Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

KW - chemoradiation

KW - dna sequencing

KW - gene methylation

KW - genetic biomarkers

KW - oesophageal cancer

KW - predictive markers

KW - COMPLEX

KW - PROTEIN

KW - PROGNOSIS

KW - ADENOCARCINOMA

KW - PREOPERATIVE CHEMORADIOTHERAPY

KW - CHEMOTHERAPY

KW - HETEROGENEITY

KW - RESISTANCE

KW - CSMD1

KW - PROGRESSION

KW - DNA sequencing

U2 - 10.1002/1878-0261.12907

DO - 10.1002/1878-0261.12907

M3 - Article

C2 - 33506581

SN - 1574-7891

VL - 15

SP - 901

EP - 914

JO - Molecular oncology

JF - Molecular oncology

IS - 4

ER -

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

Abstract

Keywords

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