Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma

BACKGROUND: Cutaneous Malignant Melanoma causes over 75% of skin cancer-related deaths, and it is clear that many factors may contribute to the outcome. Matrix Metalloproteinases (MMPs) play an important role in the degradation and remodeling of the extracellular matrix and basement membrane that, in turn, modulate cell division, migration and angiogenesis. Some polymorphisms are known to influence gene expression, protein activity, stability, and interactions, and they were shown to be associated with certain tumor phenotypes and cancer risk. METHODS: We tested seven polymorphisms within the MMP-9 gene in 1002 patients with melanoma in order to evaluate germline genetic variants and their association with progression and known risk factors of melanoma. The polymorphisms were selected based on previously published reports and their known or potential functional relevance using in-silico methods. Germline DNA was then genotyped using pyrosequencing, melting temperature profiles, heteroduplex analysis, and fragment size analysis. RESULTS: We found that reference alleles were present in higher frequency in patients who tend to sunburn, have family history of melanoma, higher melanoma stage, intransit metastasis and desmoplastic melanomas among others. However, after adjustment for age, sex, phenotypic index, moles, and freckles only Q279R, P574R and R668Q had significant associations with intransit metastasis, propensity to tan/sunburn and primary melanoma site. CONCLUSION: This study does not provide strong evidence for further investigation into the role of the MMP-9 SNPs in melanoma progression

Fusion between hematopoietic and epithelial cells in adult human intestine.

Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplanted cells have been detected in non-hematopoietic recipient cells of human liver, vascular endothelium, intestinal epithelium and brain. The underlying mechanisms by which this occurs are unclear. Evidence from mice suggests it is due in part to fusion between cells of hematopoietic and non-hematopoietic origins; however, direct evidence for this in humans is scant. Here, by quantitative and statistical analysis of X- and Y-chromosome numbers in epithelial and non-epithelial intestinal cells from gender-mismatched hematopoietic cell transplant patients, we provide evidence that transplanted cells of the hematopoietic lineage incorporate into human intestinal epithelium through cell fusion. This is the first definitive identification of cell fusion between hematopoietic cells and any epithelial cell type in humans, and provides the basis for further understanding the physiological and potential pathological consequences of cell fusion in humans

Differentiation status of cells with abnormal sex-karyotypes.

<p><b>(</b>A) FABP2/IFABP expression in a control and (B) transplant patient sample with an example of an XXY cell. Brackets indicate differentiated (high Fabp2/Ifabp expression, black brackets) and undifferentiated (low Fabp2/Ifabp expression, gray brackets) regions of epithelium within each sample. (C) Enlarged view of boxed region from <i>B</i>, in an adjacent tissue section stained for Lamin B1.(D) Enlarged view of boxed region from panel C, showing X- (green) and Y- (red) chromosomes and Lamin B1 (white). Arrowhead indicates the same nucleus in panels C and D. Dashed lines indicate boundaries of epithelial and non-epithelial compartments.</p

Frequency of nuclei with 2 or 3 X-chromosomes.

<p>Percent of Y-chromosome-positive nuclei with two or three X-chromosomes, observed in epithelial (epi) and non-epithelial (non-epi) compartments of normal male and male-into-female gender mismatched bone marrow transplant patients (transplant). *, p = 0.0016, Fisher's exact test.</p

Epithelial compartmentalization and sex-karyotyping of intestinal cells.

<p>(A) Hematoxylin and Eosin stained intestinal biopsy; epithelial compartment is labeled. (B) Adjacent tissue section to that from panel A stained for X- (green) and Y- (red) chromosomes and Lamin B1 (white). Arrows indicate Y-chromosome-positive epithelial cells and the arrowhead points to a Y-chromosome-positive non-epithelial cell. Inset shows a sub-region stained for cytokeratin (blue); arrows and arrowhead serve as positional references. (C) Enlarged views of cells indicated in panel B by arrows and arrowhead; sex-karyotype is indicated for each. (D) Independent patient sample also stained for X- (green) and Y- (red) chromosomes and Lamin B1 (white). Arrows indicate Y-chromosome-positive epithelial cells. Dashed lines in all panels indicate boundaries of epithelial and non-epithelial compartments.</p