This article reviews the main molecular alterations involved in endometrial carcinoma. Five molecular features (microsatellite instability, and mutations in the PTEN, k-RAS, PIK3CA and b-catenin genes) are characteristic of endometrioid carcinomas, whereas nonendometrioid carcinomas show alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). The review also covers the phenomenon of apoptosis resistance, as well as the results obtained from cDNA array studies, and the perspectives for targeted therapies. A group of practical applications of molecular pathology techniques are also mentioned: diagnosis of hereditary non-polyposis colon cancer syndrome in patients with endometrial carcinoma; evaluation of precursor lesions; prognosis; diagnosis, particularly for synchronous endometrioid carcinomas of the uterus and the ovaries; and targeted therapies. While OEC show microsatellite instability (MI), and mutations in the PTEN, k-RAS, PIK3CA and b-catenin genes, NOEC exhibit alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). MOLECULAR PATHOLOGY OF ENDOMETRIOID CARCINOMASMicrosatellite instability (MI) is seen in cancers (colonic, endometrial and others) of patients with hereditary non-polyposis colon cancer (HNPCC), but is also seen in 25-30% of sporadic EC. 4-8HNPCC patients with EC have an inherited germ-line mutation in MLH-1, MSH-2, MSH-6 or PMS-2 (''first hit''); but EC develops only after the instauration of a deletion or mutation in the contralateral MLH-1,MSH-2, MSH-6 or PMS-2 allele (''second hit'') in endometrial cells. Once the two hits occur, the deficient mismatch repair role of the gene (MLH-1, MSH-2, MSH-6 or PMS-2) causes the acquisition of MI, and the development of the tumour. In sporadic EC, MLH-1 inactivation by promoter hypermethylation is the main cause of mismatch repair deficiency, 9 which usually occurs at the precursor (atypical hyperplasia) lesion.10 Thus, MLH-1 hypermethylation is an early event in the pathogenesis of OEC, which precedes the development of MI. The prognostic significance of MI is under debate, but there is some convincing evidence suggesting association with favourable outcome.The instauration of MI, the so-called mutator phenotype, leads to subsequent accumulation of myriads of mutations. Short-tandem repeats, like microsatellites, are particularly susceptible to mismatch repair alterations, but they are predominantly located in non-coding DNA sequences (fig 3); and the presence of subtle mutations (insertions or deletions) does not result in the production of abnormal proteins. However, some small short-tandem repeats, like mononucleotide repeats, are sometimes located within the coding sequence of some important genes (BAX, IGFIIR, hMSH3 and hMSH6). Mutations in these tracts are interpreted as secondary events in the mutator phenotype pathway in cancers with MI, probably...

Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, PZ0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (PZ0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (PZ2.8!10 K8 ). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.

Standard antineoplastic treatment for metastatic melanoma is ineffective in the large majority of patients. Therefore, alternative approaches need to be investigated. STI571 is a new antineoplastic compound, which selectively inhibits the tyrosine kinase activity of ABL, c-Kit and platelet-derived growth factor receptor (PDGFR). Melanoma may express all of these proteins. The aim of this study was to investigate whether STI571 inhibits the in-vitro growth of melanoma cells. Nineteen cell lines were obtained from four primary and 15 metastatic melanomas of cutaneous origin. The percentages of positive cells for the putative targets of STI571 were as follows: ABL, 41-100%; c-Kit, 8-97%; PDGFR-alpha, 41-98%; PDGFR-beta, 51-99%. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium (MTT) and viability assays showed that STI571 clearly inhibits the proliferation of eight of the 19 (42.1%) cell lines. No relationship could be established between the expression of c-Kit, ABL, PDGFR-alpha or PDGFR-beta and the response of cell lines to STI571. Our study shows, for the first time, an antiproliferative effect of STI571 on human melanoma cell lines of cutaneous origin, raising the possibility of the future clinical use of STI571. The identification of the target of STI571 in human cutaneous melanoma cells would allow the selection of patients who could benefit from this treatment.

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