A molecular stratification of chilean gastric cancer patients with potential clinical applicability

Mauricio P. Pinto; Miguel Córdova-Delgado; Ignacio N. Retamal; Matías Muñoz-Medel; M. Loreto Bravo; Doris Durán; Francisco Villanueva; César Sanchez; Francisco Acevedo; Sebastián Mondaca; Erica Koch; Carolina Ibañez; Héctor Galindo; Jorge Madrid; Bruno Nervi; José Peña; Javiera Torres; Gareth I. Owen; Alejandro H. Corvalán; Ricardo Armisén; Marcelo Garrido

doi:10.3390/cancers12071863

A molecular stratification of chilean gastric cancer patients with potential clinical applicability

Mauricio P. Pinto, Miguel Córdova-Delgado, Ignacio N. Retamal, Matías Muñoz-Medel, M. Loreto Bravo, Doris Durán, Francisco Villanueva, César Sanchez, Francisco Acevedo, Sebastián Mondaca, Erica Koch, Carolina Ibañez, Héctor Galindo, Jorge Madrid, Bruno Nervi, José Peña, Javiera Torres, Gareth I. Owen, Alejandro H. Corvalán, Ricardo ArmisénMarcelo Garrido^*

^*Corresponding author for this work

Facultad de Odontología

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

15 Scopus citations

Abstract

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic.

Original language	English
Article number	1863
Pages (from-to)	1-14
Number of pages	14
Journal	Cancers
Volume	12
Issue number	7
DOIs	https://doi.org/10.3390/cancers12071863
State	Published - Jul 2020

Bibliographical note

Funding Information:
This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695).

Funding Information:
Funding: This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695).

Funding Information:
Conflicts of Interest: BN is an advisor for Roche; JM is a consultant for Boehringer-Ingelheim and provides expert testimony to Roche; CS receives research funding from Roche and Novartis, and provides expert testimony for Pfizer and have received travel or accommodations, or expenses from Novartis and Pfizer; SM is a consultant for Foundation Medicine; EK participates at the speakers’ bureau for Novartis and have received travel support from Pfizer, Novartis and Roche Pharma; MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers’ bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Epstein–Barr virus
Gastric cancer
Molecular classification
Molecular subtypes
Targeted therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers12071863

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Pinto, M. P., Córdova-Delgado, M., Retamal, I. N., Muñoz-Medel, M., Bravo, M. L., Durán, D., Villanueva, F., Sanchez, C., Acevedo, F., Mondaca, S., Koch, E., Ibañez, C., Galindo, H., Madrid, J., Nervi, B., Peña, J., Torres, J., Owen, G. I., Corvalán, A. H., ... Garrido, M. (2020). A molecular stratification of chilean gastric cancer patients with potential clinical applicability. Cancers, 12(7), 1-14. Article 1863. https://doi.org/10.3390/cancers12071863

@article{c3969b147bf3417480f91ff5b3a40042,

title = "A molecular stratification of chilean gastric cancer patients with potential clinical applicability",

abstract = "Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic.",

keywords = "Epstein–Barr virus, Gastric cancer, Molecular classification, Molecular subtypes, Targeted therapy, Epstein–Barr virus, Gastric cancer, Molecular classification, Molecular subtypes, Targeted therapy",

author = "Pinto, {Mauricio P.} and Miguel C{\'o}rdova-Delgado and Retamal, {Ignacio N.} and Mat{\'i}as Mu{\~n}oz-Medel and Bravo, {M. Loreto} and Doris Dur{\'a}n and Francisco Villanueva and C{\'e}sar Sanchez and Francisco Acevedo and Sebasti{\'a}n Mondaca and Erica Koch and Carolina Iba{\~n}ez and H{\'e}ctor Galindo and Jorge Madrid and Bruno Nervi and Jos{\'e} Pe{\~n}a and Javiera Torres and Owen, {Gareth I.} and Corval{\'a}n, {Alejandro H.} and Ricardo Armis{\'e}n and Marcelo Garrido",

note = "Funding Information: This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: Funding: This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: Conflicts of Interest: BN is an advisor for Roche; JM is a consultant for Boehringer-Ingelheim and provides expert testimony to Roche; CS receives research funding from Roche and Novartis, and provides expert testimony for Pfizer and have received travel or accommodations, or expenses from Novartis and Pfizer; SM is a consultant for Foundation Medicine; EK participates at the speakers{\textquoteright} bureau for Novartis and have received travel support from Pfizer, Novartis and Roche Pharma; MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers{\textquoteright} bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = jul,

doi = "10.3390/cancers12071863",

language = "English",

volume = "12",

pages = "1--14",

journal = "Cancers",

issn = "2072-6694",

publisher = "MDPI Multidisciplinary Digital Publishing Institute",

number = "7",

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Pinto, MP, Córdova-Delgado, M, Retamal, IN, Muñoz-Medel, M, Bravo, ML, Durán, D, Villanueva, F, Sanchez, C, Acevedo, F, Mondaca, S, Koch, E, Ibañez, C, Galindo, H, Madrid, J, Nervi, B, Peña, J, Torres, J, Owen, GI, Corvalán, AH, Armisén, R & Garrido, M 2020, 'A molecular stratification of chilean gastric cancer patients with potential clinical applicability', Cancers, vol. 12, no. 7, 1863, pp. 1-14. https://doi.org/10.3390/cancers12071863

TY - JOUR

T1 - A molecular stratification of chilean gastric cancer patients with potential clinical applicability

AU - Pinto, Mauricio P.

AU - Córdova-Delgado, Miguel

AU - Retamal, Ignacio N.

AU - Muñoz-Medel, Matías

AU - Bravo, M. Loreto

AU - Durán, Doris

AU - Villanueva, Francisco

AU - Sanchez, César

AU - Acevedo, Francisco

AU - Mondaca, Sebastián

AU - Koch, Erica

AU - Ibañez, Carolina

AU - Galindo, Héctor

AU - Madrid, Jorge

AU - Nervi, Bruno

AU - Peña, José

AU - Torres, Javiera

AU - Owen, Gareth I.

AU - Corvalán, Alejandro H.

AU - Armisén, Ricardo

AU - Garrido, Marcelo

N1 - Funding Information: This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: Funding: This research was funded by FONDECYT, grant number 1180173. MC-D is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: Conflicts of Interest: BN is an advisor for Roche; JM is a consultant for Boehringer-Ingelheim and provides expert testimony to Roche; CS receives research funding from Roche and Novartis, and provides expert testimony for Pfizer and have received travel or accommodations, or expenses from Novartis and Pfizer; SM is a consultant for Foundation Medicine; EK participates at the speakers’ bureau for Novartis and have received travel support from Pfizer, Novartis and Roche Pharma; MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers’ bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/7

Y1 - 2020/7

N2 - Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic.

AB - Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic.

KW - Epstein–Barr virus

KW - Gastric cancer

KW - Molecular classification

KW - Molecular subtypes

KW - Targeted therapy

KW - Epstein–Barr virus

KW - Gastric cancer

KW - Molecular classification

KW - Molecular subtypes

KW - Targeted therapy

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U2 - 10.3390/cancers12071863

DO - 10.3390/cancers12071863

M3 - Article

AN - SCOPUS:85088917444

SN - 2072-6694

VL - 12

SP - 1

EP - 14

JO - Cancers

JF - Cancers

IS - 7

M1 - 1863

ER -

A molecular stratification of chilean gastric cancer patients with potential clinical applicability

Abstract

Bibliographical note

Keywords

UN SDGs

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