Early studies of the clonal status of parathyroid tumors assessed X-chromosome inactivation patterns by measuring isoforms of glucose-6-phopshate dehydrogenase in parathyroid adenomas of women heterozygous for the polymorphism. These stud­ies indicated that parathyroid adenomas were polyclonal as op­posed to monoclonal growths. The issue of the clonal status of parathyroid tumors was reevaluated several years later, again by X- chromosome inactivation method, using a DNA polymor­phism-based method that avoids many of the pitfalls of the previ­ously protein polymorphism approach. It was demonstrated that most, if not all, parathyroid adenomas are monoclonal tumors. This finding is consistent with the general experience that surgical removal of such tumors is curative of the disease. Parathyroid carcinomas, as would be expected, are also mono­clonal. Monoclonality is a reflection of the selective advantage gained by a parathyroid cell when a sufficient number of critical changes in protooncogenes and/or tumor suppressor genes oc­cur within it. Progeny of such a cell grows and accumulates addi­tional genetic changes (this is clonal evolution), ultimately form­ing a clinically apparent mass of cells.

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Introduction

Over the past ten years, our knowledge of the molecular basis of parathyroid neoplasia has increased substantially. Many of the well established general themes in tumor biology appear to be applicable to parathyroid tumorigenesis, in spite of the typi­cally nonmalignant status of these tumors. Patients with primary hyperparathyroidism (PHPT) have both an increased parathy­roid proliferation and a resetting of the control of PTH secretion (set-point abnormality). A full molecular description of parathyroid tumor biology will need to explain these phenomena and other special aspects such as the role of irradiation in pre­disposing to parathyroid tumors, the rarity of parathyroid cancer as compared with the abundance of benign parathyroid lesion, and the possible role of the post menopause and/or estrogen status.

It is now clear that neoplasia is a genetic disease, in which the DNA damage occurs somatically and is typically not inherited or present in the germ cells. In general, multiple mutations (ac­cumulating within the same cell and its progeny) are required for the emergence and progression of the clonal status. Fur­thermore, the monoclonality of tumors implies that the needed accumulation of mutations occurs only rarely in a large popula­tion of cells in a tissue.

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The precursor lesions of invasive adenocarcinoma of the gallbladder have recently been recognized as those of in­testinal metaplasia, dysplasia and carcinoma in situ. The adenoma-carcinoma sequence occurs only in a minority of cases. Recognition of these lesions is, therefore, important when removing gallbladders for cholecystitis or cholelithia­sis.

Some gallbladder adenocarcinomas are immunoreactive for alpha-fetoprotein. No such case occurred in our se­ries.

The bcl-2 gene product is an integral membrane protein located in the inner mitochondrial membrane and princi­pally exerts its effect on the cell cycle as a suppressor of apop- tosis. Bcl-2 protein expression is linked to long term survival in female breast carcinomas. In our series, no such linkage could be established because all cases were immunonegative to Bcl-2 staining.

Our study showed moderate to strong staining patterns of CEA in both the in situ and invasive components. Such pat­terns were also associated with low mean survival rates. The pattern of CEA distribution in the gallbladder is similar to that of the rest of the digestive tract. Normal epithelial cells contain small quantities of CEA that are always distributed along the apical cytoplasm. At least three CEA-related macromolecules, glycoprotein types I, II and III, are found in normal bile. Type I occurs in normal bile and is similar to CEA but lacks the tumour-associated antigenic determi­nants. In inflammatory and tumorous conditions, type I is re­placed with types II and III, the latter being immunologically similar to CEA. The amount of CEA progressively increases in dysplasia, in situ lesions and invasive carcinomas. In addi­tion to a stronger staining, CEA can also be seen within the cytoplasm and even within the gland secretions in the inva­sive components. It is possible that serological assess­ment of CEA may be of value in the close follow-up of such precursor lesions . Such altered CEA staining pattern seems to reflect an early event in the progression of the disease as reflected by increased staining in both in situ and invasive components of the tumour in the majority of cases. Cases with negative staining in the frankly invasive components further demonstrate that cellular antigens are both devel­oped and lost during the process of neoplastic transformation of the gallbladder.

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The staining to alpha-fetoprotein and Bcl-2 antibodies re­mained consistently negative to very weak in all parts of the tumour in all cases. Moderate to strong P53 staining was ob­served in 17 (89%) of the in situ component and 24 (86%) of the invasive components (Table 2). CEA staining was ob­served in both the in situ (84%) and invasive (89%) compo­nents (Table 3). The immunoreaction was strong and present along the cell surface, within the cytoplasm and in the gland secretions (Figures 3A,B).

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Gallbladder carcinomas: An immunoprognostic evaluation of P53, Bcl-2, CEA and alpha-fetoprotein

Cancer of the gallbladder is the fifth most common can­cer of the digestive tract. The mean five-year survival rate has remained at 1% despite surgical intervention; this is mainly attributed to its late presentation, with extensive lo­cal spread and concomitant invasion of the liver. It is now accepted that most cases of invasive gallbladder cancers arise from precursor lesions of intestinal metaplasia, dysplasia and carcinoma in situ lesions. The adenoma-cancer sequence is recognized in the minority of cases. In this study, the expres­sion of P53, Bcl-2, carcinoembryonic antigen (CEA) and alpha-fetoprotein was evaluated in both the in situ and inva­sive components of the tumour, and the results were corre­lated with their mean survival.

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Similarly to other genes polymorphisms, significant differ­ences exist in VDR polymorphisms distribution among differ­ent ethnic groups. A possible explanation to polymorphism generation phenomena is DNA damage events in an ancient small population that grow up in frequency becoming poly­morphisms in modern populations. VDR haplotypes distribu­tion reflects out-of-Africa evolution theory that describe hu­man populations origin and dispersion around the world, where gene-environment interactions favours the survival of some allelic variants. Old polymorphisms might show large population/ethnic variability (FokI), while new ones are likely characterized by small population variability (Cdx2). Assum­ing that a polymorphism should have the same functional ef­fect in different ethnic groups, different allele frequencies across these groups may explain differences in the incidence of pathologies and variability on drug response among them (i.e. Asians seem to be more vitamin D-sensitive while Cau­casians appear more oestrogen-sensitive than other ethnic groups). In the case of non-functional polymorphisms, fre­quencies of these markers are very different among ethnic groups. It is also difficult to understand consequences of eth­nic allele variation in this case, because of environmental fac­tors interference, such as diet and physical exercise. This emphasises that an haplotypes map of VDR polymorphisms in different ethnic groups is necessary.

Functionality of VDR polymorphisms

Functional studies are needed to determinate the way certain haplotypes in a candidate gene affects protein function. Com­pared to the larger number of genetic association studies, there has been little published on the mechanism through which VDR gene polymorphisms might influence VDR receptor functionality.

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