Colorectal cancer heterogeneity from a gene expression
perspective

a 2013

Colorectal cancer heterogeneity from a gene expression perspective

BUDINSKÁ, Eva, Andrea JANOTOVÁ, sabine TEJPAR, Vlad POPOVICI, Giovanni D’ARIO et. al.

Basic information

Original name

Colorectal cancer heterogeneity from a gene expression perspective

Authors

Edition

AACR 2013 Annual Meeting, 2013

Other information

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Organization unit

Faculty of Medicine

Keywords (in Czech)

kolorektální karcinom, genová exprese, podtypy, histopatologie

Keywords in English

colroectal cancer, gene expression, subtypes, histopathology

Abstract

V originále

In a robust and unsupervised analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets we defined a set of five gene expression subtypes which were validated in an independent set of 720 samples. We tested these subtypes with common clinico-pathological features, copy number variations, mutations in key cancer associated genes - such as BRAF or KRAS - and prognosis, and found important associations. The gene set enrichment analysis of groups of genes with similar gene expression patterns and existing CRC signatures followed by the literature search of gene members identified a number of biological motifs underlying the CRC gene expression heterogeneity, such as EMT/stroma, immune, proliferation, Wnt signaling, 20q chromosome, markers of enterocytes, secretory cell markers or lipid synthesis. Based on these results we named the subtypes A: Surface crypt, B: Lower crypt, C: CIMP-H-like, D: Mesenchymal and E: Mixed. Subtype A, specific by expression of markers of differentiated colon crypt cells was enriched for KRAS mutant tumors (77%); WNT-high proliferative subtype B had a good prognosis and comprised mainly MSS (100%) and left (76%); subtype C had the worse prognosis in SAR and was enriched for BRAFm (29%), right (73%), MSI (60%) and mucinous (38%) tumors. Subtype D, with the worse prognosis in OS and RFS was characteristic by high expression of EMT/stroma genes and subtype E enriched for p53 mutations (73%). We performed nuclear beta-catenin immunoreactivity scoring of paraffin sections of 133 samples and found significant associations with the subtypes. The supervised histopathological assessment of the same set of paraffin sections resulted in an identification of subtype specific morphological patterns (serrated and papillary pattern in subtype A, complex tubular pattern in subtypes B and E, solid and mucinous in subtype C, desmoplastic reaction in D). Next, we concentrated our efforts on gene networks analysis in order to identify subtype specific gene-gene interactions. These results further refined between-subtype differences. The proposed CRC characterization provides a molecular basis to different morphological patterns in CRC and the identified molecular motifs allow subtypes to be further interrogated functionally in vitro for driving oncogenic events.

Citovat

BUDINSKÁ, Eva, Andrea JANOTOVÁ, sabine TEJPAR, Vlad POPOVICI, Giovanni D’ARIO, Nicolas LAPIQUE, Sikora KATARZYNA OTYLIA, Di Narzo ANTONIO FABIO, Yan PU, Hodgson JOHN GRAEME, Weinrich SCOTT, Bosman FRED, Roth ARNAUD and Delorenzi MAURO. Colorectal cancer heterogeneity from a gene expression perspective. In AACR 2013 Annual Meeting. 2013.

@proceedings{1102545,
   author = {Budinská, Eva and Janotová, Andrea and Tejpar, sabine and Popovici, Vlad and D’Ario, Giovanni and Lapique, Nicolas and Katarzyna Otylia, Sikora and Antonio Fabio, Di Narzo and Pu, Yan and John Graeme, Hodgson and Scott, Weinrich and Fred, Bosman and Arnaud, Roth and Mauro, Delorenzi},
   booktitle = {AACR 2013 Annual Meeting},
   keywords = {colroectal cancer, gene expression, subtypes, histopathology},
   language = {eng},
   title = {Colorectal cancer heterogeneity from a gene expression perspective},
   url = {http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2013.aspx},
   year = {2013}
}

TY  - CONF
ID  - 1102545
AU  - Budinská, Eva - Janotová, Andrea - Tejpar, sabine - Popovici, Vlad - D’Ario, Giovanni - Lapique, Nicolas - Katarzyna Otylia, Sikora - Antonio Fabio, Di Narzo - Pu, Yan - John Graeme, Hodgson - Scott, Weinrich - Fred, Bosman - Arnaud, Roth - Mauro, Delorenzi
PY  - 2013
TI  - Colorectal cancer heterogeneity from a gene expression perspective
KW  - colroectal cancer, gene expression, subtypes, histopathology
UR  - http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2013.aspx
N2  - In a robust and unsupervised analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets we defined a set of five gene expression subtypes which were validated in an independent set of 720 samples. We tested these subtypes with common clinico-pathological features, copy number variations, mutations in key cancer associated genes - such as BRAF or KRAS - and prognosis, and found important associations. The gene set enrichment analysis of groups of genes with similar gene expression patterns and existing CRC signatures followed by the literature search of gene members identified a number of biological motifs underlying the CRC gene expression heterogeneity, such as EMT/stroma, immune, proliferation, Wnt signaling, 20q chromosome, markers of enterocytes, secretory cell markers or lipid synthesis. Based on these results we named the subtypes A: Surface crypt, B: Lower crypt, C: CIMP-H-like, D: Mesenchymal and E: Mixed. Subtype A, specific by expression of markers of differentiated colon crypt cells was enriched for KRAS mutant tumors (77%); WNT-high proliferative subtype B had a good prognosis and comprised mainly MSS (100%) and left (76%); subtype C had the worse prognosis in SAR and was enriched for BRAFm (29%), right (73%), MSI (60%) and mucinous (38%) tumors. Subtype D, with the worse prognosis in OS and RFS was characteristic by high expression of EMT/stroma genes and subtype E enriched for p53 mutations (73%). We performed nuclear beta-catenin immunoreactivity scoring of paraffin sections of 133 samples and found significant associations with the subtypes. The supervised histopathological assessment of the same set of paraffin sections resulted in an identification of subtype specific morphological patterns (serrated and papillary pattern in subtype A, complex tubular pattern in subtypes B and E, solid and mucinous in subtype C, desmoplastic reaction in D). Next, we concentrated our efforts on gene networks analysis in order to identify subtype specific gene-gene interactions. These results further refined between-subtype differences. The proposed CRC characterization provides a molecular basis to different morphological patterns in CRC and the identified molecular motifs allow subtypes to be further interrogated functionally in vitro for driving oncogenic events.
ER  -

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