Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy

open here please ► Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy: "Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy

* Iain Beehuat Tan
Affiliations
o Department of Medical Oncology, , National Cancer Centre Singapore, Singapore
o National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore
o Duke-National University of Singapore Graduate Medical School, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Tatiana Ivanova
Affiliations
o Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Kiat Hon Lim
Affiliations
o Department of Pathology, Singapore General Hospital, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Chee Wee Ong
Affiliations
o Cancer Science Institute, National University of Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Niantao Deng
Affiliations
o Duke-National University of Singapore Graduate Medical School, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Julian Lee
Affiliations
o Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Sze Huey Tan
Affiliations
o Genome Institute of Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Jeanie Wu
Affiliations
o Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Ming Hui Lee
Affiliations
o Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Chia Huey Ooi
Affiliations
o Duke-National University of Singapore Graduate Medical School, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Sun Young Rha
Affiliations
o Department of Internal Medicine, Yonsei Cancer Center, Seoul, South Korea
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Wai Keong Wong
Affiliations
o Department of General Surgery, Singapore General Hospital, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Alex Boussioutas
Affiliations
o Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Khay Guan Yeoh
Affiliations
o Department of Medicine, National University Health System, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Jimmy So
Affiliations
o Department of Surgery, National University Health System, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Wei Peng Yong
Affiliations
o Cancer Science Institute, National University of Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Akira Tsuburaya
Affiliations
o Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Heike Grabsch
Affiliations
o Department of Pathology and Tumour Biology, Leeds Institute for Molecular Medicine, Leeds, England
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Han Chong Toh
Affiliations
o Department of Medical Oncology, , National Cancer Centre Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Steven Rozen
Affiliations
o Duke-National University of Singapore Graduate Medical School, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Jae Ho Cheong
Affiliations
o Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Sung Hoon Noh
Affiliations
o Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Wei Kiat Wan
Affiliations
o Department of Pathology, Singapore General Hospital, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Jaffer A. Ajani
Affiliations
o Department of GI Oncology, MD Anderson Cancer Center, Houston, Texas
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Ju–Seog Lee
Affiliations
o Department of Systems Biology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Manuel Salto Tellez
Affiliations
o Cancer Science Institute, National University of Singapore, Singapore
o Department of Pathology, National University Health System, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
* , Patrick Tan
Affiliations
o Duke-National University of Singapore Graduate Medical School, Singapore
o Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
o Cancer Science Institute, National University of Singapore, Singapore
o Genome Institute of Singapore, Singapore
o Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
o Corresponding Author InformationReprint requests Address requests for reprints to: Patrick Tan, 8 College Road, Singapore 169857, Republic of Singapore. fax: (65) 62265294
email address

Received 10 May 2010; accepted 15 April 2011. published online 29 April 2011.


Background & Aims

Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs.

Methods

We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed.

Results

Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil–based therapy.

Conclusions

Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.

Keywords: Microarray Analysis, Pharmacogenomics, mRNA, Stomach, Carcinogenesis

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Actualidad Ultimas noticias - JANOes y agencias - Identifican dos subtipos genicos de cancer de estomago - JANO.es - ELSEVIER: "ONCOLOGÍA
Identifican dos subtipos génicos de cáncer de estómago

JANO.es y agencias · 02 Agosto 2011 13:11


El hallazgo añade una mayor especificidad a las clasificaciones microscópicas de que se disponía y ofrece orientación a los médicos para afinar la personalización del tratamiento.

Existen dos variaciones del cáncer de estómago según la composición genética y cada uno responde de manera diferente a la quimioterapia, según ha demostrado un equipo de científicos liderado por investigadores de la Universidad Duke-Nacional, en Singapur. El hallazgo, publicado en Gastroenterology, constituye el primer análisis genómico a gran escala del cáncer gástrico que confirma los dos tipos de tumor.

'Nuestro estudio es el primero en demostrar que una propuesta de clasificación molecular del cáncer gástrico puede identificar subtipos genómicos que responden de manera diferente a las terapias, lo cual es crucial en los esfuerzos para personalizar los tratamientos', afirma el doctor Patrick Tan, autor principal del estudio y profesor del Cancer and Stem Cell Biology Program en la Universidad Duke-Nacional.

Se estima que 21.000 personas en Estados Unidos serán diagnosticadas con cáncer de estómago durante este año y 10.570 morirán a causa de la enfermedad, según el National Cancer Institute. A nivel mundial, sólo el cáncer de pulmón es más letal.

Los hallazgos genéticos realizados por los investigadores añaden una mayor especificidad a las clasificaciones microscópicas y, por primera vez, ofrecen orientación a los médicos para recetar tratamientos eficaces. El equipo de investigación analizó primero 37 líneas celulares de cáncer gástrico, células de cáncer puras libres de sangre, tejido y otras adulteraciones que pudieran afectar a los resultados.

Los perfiles de expresión génica produjeron patrones muy distintos que indicaban los dos subtipos. En el 64% de los casos, los subtipos genéticos validaron la clasificación de Lauren -una prueba microscópica desarrollada en los años sesenta. En el 36% restante, el proceso genómico distinguió subtipos que la anterior prueba patológica no puedo distinguir. Los resultados fueron confirmados mediante muestras de tumores de 521 pacientes con cáncer.

Patrones moleculares distintos

'Fue muy reconfortante para nosotros que los subtipos genómicos se asociaran con el sistema de Lauren', comenta Tan, 'existía la creencia general de que el cáncer gástrico, ya fuera intestinal o difuso (según la clasificación de Lauren), representaba dos versiones muy diferentes de cáncer gástrico, y ahora los datos genómicos lo confirman mediante la demostración de que los dos subtipos tienen patrones moleculares muy diferentes.'

El establecimiento de la precisa definición de los subtipos de tumores permitió a los investigadores observar las diferentes respuestas a la quimioterapia. Los tumores de tipo intestinal mostraron una respuesta significativamente mejor a la quimioterapia con 5-fluorouracilo y oxaliplatino, y eran más resistentes al cisplatino que los tumores difusos.

'Las razones exactas de esta diferencia son poco claras, y ésta es un área en la que estamos trabajando', comenta Tan, que agrega que los investigadores están trabajando para encontrar las vulnerabilidades específicas de los subtipos moleculares a los diferentes tratamientos.


Gastroenterology (2011); doi:10.1053/j.gastro.2011.04.042
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