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Am J Transl Res 2012;4(3):279-290
Original Article
Single nucleotide polymorphisms of the adult intestinal stem cell
marker Lgr5 in primary and metastatic colorectal cancer
Britta Kleist, Li Xu, Christian Kersten, Violetta Seel, Guojun Li, Micaela Poetsch
Department of Pathology and Department of Oncology, Southern Hospital Trust, Kristiansand, Norway;
Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas,
USA; Institute of Legal Medicine, University Hospital Essen, Essen, Germany
Received June 4, 2012; accepted June 29, 2012; Epub July 20, 2012; Published August 15, 2012
Abstract: Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic
variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in
normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV
colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression
analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5
genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and
distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein
expression (p=0.0394), which mainly can be attributed to the negative influence of non-coding Lgr5 gene
variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary
tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival
and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary
and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small
sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5
protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary
tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly
prognostic importance, which has to be further evaluated by large cohort studies. (AJTR1206003).
Keywords: Colorectal cancer, metastases, Lgr5, stem cell like cells, allelic variation
Address all correspondence to:
Dr. Britta Kleist
Department of Pathology
Soerlandet sykehus HF
4604 Kristiansand, Norway.
Tel: +47 3807 3071; Fax: +47 3807 3076
E-mail: britta.kleist@sshf.no
Original Article
Single nucleotide polymorphisms of the adult intestinal stem cell
marker Lgr5 in primary and metastatic colorectal cancer
Britta Kleist, Li Xu, Christian Kersten, Violetta Seel, Guojun Li, Micaela Poetsch
Department of Pathology and Department of Oncology, Southern Hospital Trust, Kristiansand, Norway;
Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas,
USA; Institute of Legal Medicine, University Hospital Essen, Essen, Germany
Received June 4, 2012; accepted June 29, 2012; Epub July 20, 2012; Published August 15, 2012
Abstract: Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic
variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in
normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV
colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression
analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5
genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and
distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein
expression (p=0.0394), which mainly can be attributed to the negative influence of non-coding Lgr5 gene
variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary
tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival
and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary
and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small
sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5
protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary
tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly
prognostic importance, which has to be further evaluated by large cohort studies. (AJTR1206003).
Keywords: Colorectal cancer, metastases, Lgr5, stem cell like cells, allelic variation
Address all correspondence to:
Dr. Britta Kleist
Department of Pathology
Soerlandet sykehus HF
4604 Kristiansand, Norway.
Tel: +47 3807 3071; Fax: +47 3807 3076
E-mail: britta.kleist@sshf.no
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