Distinct gene expression signatures in lynch syndrome and familial colorectal cancer type x.
BACKGROUND
Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.


OBJECTIVE
We addressed the gene expression signatures in colorectal cancer linked to Lynch syndrome and FCCTX with the aim to identify candidate genes and to map signaling pathways relevant in hereditary colorectal carcinogenesis.


METHODS
The 18 k whole-genome c-DNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay was applied to 123 colorectal cancers, including 39 Lynch syndrome tumors and 37 FCCTX tumors. Target genes were technically validated using real-time quantitative RT-PCR (qRT-PCR) and the expression signature was validated in independent datasets.


RESULTS
Colorectal cancers linked to Lynch syndrome and FCCTX showed distinct gene expression profiles, which by significance analysis of microarrays (SAM) differed by 2188 genes. Functional pathways involved were related to G-protein coupled receptor signaling, oxidative phosphorylation, and cell cycle function and mitosis. qRT-PCR verified altered expression of the selected genes NDUFA9, AXIN2, MYC, DNA2 and H2AFZ. Application of the 2188-gene signature to independent datasets showed strong correlation to MMR status.


CONCLUSIONS
Distinct genetic profiles and deregulation of different canonical pathways apply to Lynch syndrome and FCCTX and key targets herein may be relevant to pursue for refined diagnostic and therapeutic strategies in hereditary colorectal cancer.
Department of Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden. mev_dv@yahoo.com
Mev
M
Dominguez-Valentin
Christina
C
Therkildsen
Srinivas
S
Veerla
Mats
M
Jönsson
Inge
I
Bernstein
Ake
A
Borg
Mef
M
Nilbert
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015203:Reproducibility of Results; D015398:Signal Transduction; D059467:Transcriptome