Copy number alterations of the epidermal growth factor receptor (EGFR) gene have been extensively analyzed in different cancers, but no data are available for primary malignant melanoma. The aim of the present study was to simultaneously investigate the EGFR gene and chromosome 7 copy number alterations in 81 cutaneous malignant melanomas by interphase FISH and correlate the data with clinicopathological parameters of patients. EGFR mRNA levels were detected by Affymetrix GeneChip Human Genome U133 Plus 2.0 expression arrays for 16 lesions. Both increased gene dosage and chromosome 7 alterations were found in 70% of tumors. Extra EGFR copies were detected in an additional 10% of samples. Polysomy 7 was associated with EGFR gene amplification. Significant correlation was found between EGFR alterations and histological subtypes, tumor thickness, ulceration and metastases formation. Amplification was significantly higher in lesions that developed metastases within 2 years after surgical excision of the primary tumor. Gene copy alterations were associated with elevated mRNA expression in 77% of lesions when compared to tumors with disomic EGFR status, the correlation was not directly proportional to gene copy number. Associations between protein expression and mRNA levels were even less prominent. In conclusion, our study indicates that amplification of the EGFR gene and polysomy 7 are frequent alterations in primary melanomas and are associated with bad prognosis. Further studies are required to clarify whether melanoma patients with EGFR alterations can benefit from anti‐EGFR therapy. © 2007 Wiley‐Liss, Inc.

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.

The pathogenesis of ovarian carcinomas is heterogeneous, with even the same entities showing great variance. In our study we investigated the mutations of the BRAF, KRAS, and p53 genes in serous and mucinous borderline tumors and in low grade and high grade serous and mucinous tumors. The mutations of BRAF and KRAS genes have been shown in 60% of borderline and low grade (well differentiated) serous and mucinous tumors, but very rarely in high grade (moderately and poorly differentiated) carcinomas. However mutations of p53 are very common in high grade tumors and this indicates a "dualistic" model of ovarian tumorigenesis. A total of 80 serous tumors, including serous borderline, low grade and high grade tumors, and 23 mucinous tumors, including borderline and invasive tumors were analysed for BRAF and KRAS mutations using real time PCR method followed by melting point analysis. P53 mutation was investigated by immunohistochemistry. We assumed mutation of the p53 gene when 100% of tumor cells showed strong nuclear positivity. We observed differences in genetic alterations in the development of the low grade tumors and between low and high grade tumors too. In some bilateral or stage II-III cases we observed differences between the mutation status of the left and right ovarian tumors and between the primary tumor and its implants. In one case in a tumor with micropapillary pattern showing high grade nuclear atypia we could detect mutations in both KRAS and p53 genes. The majority of our mucinous ovarian tumor cases showed a KRAS mutation. We have not found mutations of the BRAF and p53 genes in these cases. We have found as have others, that there is a dualistic pathway of ovarian carcinogenesis. In the majority of cases, low grade epithelial tumors develop in a stepwise manner due to genetic alterations of the members of MAP-kinase pathway; however mutation of the p53 gene is the key event in the development of high grade tumors.

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