Search

Purpose: We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene. Methods: We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3. Results: Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one. Conclusion: We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations. [ABSTRACT FROM AUTHOR]

Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were inclu ded. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is unive rsally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin. [ABSTRACT FROM AUTHOR]

Background and Objective: Parathyroid carcinoma (PC) is a rare malignant neoplasm with a relatively poor prognosis. The loss of parafibromin expression or the presence of CDC73 mutation has been found to be remarkably associated with malignancy in parathyroid tumours. However, the prognostic role of them in PC has not yet been shown due to sampling limitations. We conducted a systematic review and meta‐analysis based on individual patient data to clarify the performance of parafibromin immunohistochemical staining and CDC73 gene sequencing in predicting outcomes for patients PC. Methods: Published studies from PubMed/MEDLINE, EMBASE, Cochrane and Scopus Databases were searched using the terms 'parafibromin', 'CDC73', 'HRPT2' and 'parathyroid' to identify eligible studies. From the included studies, the survival data of patients with PC were extracted, and a Cox proportional hazards model was used to assess hazard ratio (HR) for disease‐free survival (DFS) and overall survival (OS). Results: A total of 193 patients from 9 studies were included in this survival analysis. Negative immunohistochemical staining of parafibromin was shown to be a risk factor for recurrence/metastasis (HR 2.73, P =.002) and death (HR 2.54, P =.004). Patient age ≥ 50 years was significantly related to lower OS (HR 2.37, P =.004) but not to DFS. CDC73 mutation was not statistically related to DFS or OS. Conclusions: Negative parafibromin staining indicated a higher risk of recurrence/metastasis and mortality. The immunohistochemical staining of parafibromin seems to be more promising in predicting outcomes for patients with PC than the sequencing of CDC73. [ABSTRACT FROM AUTHOR]

Inactivating mutations that lead to loss of heterozygosity within the HRPT2/Cdc73 gene are directly linked to the development of primary hyperparathyroidism, parathyroid adenomas, and ossifying fibromas of the jaw (HPT-JT). The protein product of the Cdc73 gene, parafibromin, is a core member of the polymerase-associated factors (PAF) complex, which coordinates epigenetic modifiers and transcriptional machinery to control gene expression. We conditionally deleted Cdc73 within mesenchymal progenitors or within mature osteoblasts and osteocytes to determine the consequences of parafibromin loss within the mesenchymal lineage. Homozygous deletion of Cdc73 via the Dermo1-Cre driver resulted in embryos which lacked mesenchymal organ development of internal organs, including the heart and fetal liver. Immunohistochemical detection of cleaved caspase-3 revealed extensive apoptosis within the progenitor pools of developing organs. Unexpectedly, when Cdc73 was homozygously deleted within mature osteoblasts and osteocytes (via the Ocn-Cre driver), the mice had a normal life span but increased cortical and trabecular bone. OCN-Cre;Cdc73 flox/flox bones displayed large cortical pores actively undergoing bone remodeling. Additionally the cortical bone of OCN-Cre;Cdc73 flox/flox femurs contained osteocytes with marked amounts of cytoplasmic RNA and a high rate of apoptosis. Transcriptional analysis via RNA-seq within OCN-Cre;Cdc73 flox/flox osteoblasts showed that loss of Cdc73 led to a derepression of osteoblast-specific genes, specifically those for collagen and other bone matrix proteins. These results aid in our understanding of the role parafibromin plays within transcriptional regulation, terminal differentiation, and bone homeostasis. [ABSTRACT FROM AUTHOR]

Parathyroid carcinoma has always been difficult to diagnose pathologically. In fact, most parathyroid tumors which are classified as carcinoma do not recur after excision, and most parathyroid tumors which actually metastasize or recur repeatedly in the neck are not recognized as malignant at first presentation. In 2002, germline HRPT2 (also known as CDC73) mutation was reported as the cause of hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant hereditary tumor syndrome associated with a lifetime risk of parathyroid carcinoma approaching 15 %. Subsequently, bi-allelic inactivation or mutation of HRPT2 has been reported in the majority of parathyroid carcinomas that actually behave in a malignant manner but very rarely in sporadic benign parathyroid disease. Furthermore, germline testing for HRPT2 mutation in patients presenting with parathyroid carcinoma often identifies occult HPT-JT syndrome even in the absence of a family history or other syndromic manifestations. HRPT2 mutation testing is not readily available, and loss of expression of parafibromin (the protein encoded by HRPT2) as determined by immunohistochemistry has been used as a surrogate marker of HRPT2 mutation. Immunohistochemistry for parafibromin can be technically difficult and has been deployed by different investigators with variable enthusiasm and success. However, proponents have found immunohistochemistry for parafibromin useful to definitively confirm a pathological diagnosis of parathyroid carcinoma, predict a worse outcome in definite parathyroid carcinomas, triage formal genetic testing for HPT-JT syndrome, and predict the outcome of histologically atypical parathyroid adenomas. [ABSTRACT FROM AUTHOR]

Introduction: The definitive diagnosis of parathyroid cancer is extremely difficult, from the clinical approach to the molecular diagnosis. A gene mutation was detected recently in patients with parathyroid cancer. It is a suppressor tumor gene called HRPT2, which codifies for a protein that participates in PAF1 complex, the parafibromin. It has been observed that the expression of this protein it's altered in parathyroid cancer, what would serve like method of diagnosis by immunohystochemistry, with a sensitivity and specificity of 73-96% and 99-100%, respectively. Material and Method: The anti-parafibromin immunohystochemistry staining was made in 23 parathyroids tissue samples (5 adenomas, 6 hyperplasia, 7 normal and 5 carcinomas). Results: A positive pattern is observed in almost 100% of benign pathology and 100% in normal tissue. In the cases of carcinoma only 2 of 5 had a strong positivity. Conclusions: The pathological clinical correlation does not allow the association of the loss of parafibromin immunoreactivity in some unequivocal cases of parathyroid cancer. The parafibromin immunostaining does not allow to discriminate between benign or malign pathologies. [ABSTRACT FROM AUTHOR]

Objective: To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort. Methods: Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) ( n = 15), atypical adenoma (AA) ( n = 14) and typical adenoma (TA) ( n = 17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive. Results: Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors. Median follow up times were 88 months for CA, 76 months for AA, and 104 months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma. Conclusions: Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210 months. [ABSTRACT FROM AUTHOR]

Hyperparathyroidism 2 (HRPT2) gene mutations underlie hereditary and sporadic forms of primary hyperparathyroidism (PHPT), and the encoded product parafibromin has been established as a marker for facilitating parathyroid tumour classification. HRPT2 mutations and reduced nuclear expression of parafibromin are readily observed in parathyroid carcinomas but rarely in benign tumours, thereby aiding the identification of malignant PHPT. Recently, parafibromin has been shown to localize to the nucleolar compartment, and nucleolar parafibromin exhibits tumour-suppressive properties in vitro. In this study, nucleolar parafibromin immunoreactivity was assessed by high-power magnification microscopy in 82 parathyroid tumours previously analysed for nuclear parafibromin, including 23 carcinomas, 16 atypical adenomas, and 43 adenomas. Absent nucleolar expression was evident in three carcinomas and in one atypical adenoma, which also showed expression of nuclear parafibromin in all or subsets of the tumour cells. All three carcinomas carried HRPT2-inactivating mutations predicted to abolish the three nucleolar localization signals of parafibromin. The demonstrated absence of nucleolar parafibromin in three carcinomas with HRPT2 mutations suggests that parafibromin exhibits nucleolar tumour suppressor properties also in vivo, and disruption of nucleolar localization might propel parathyroid tumorigenesis independent of nuclear parafibromin expression. The loss of nucleolar staining in the presence of nuclear parafibromin suggests that parafibromin immunoreactivity should also be assessed in the nucleoli, as the sensitivity for the detection of malignant and atypical PHPT is increased compared to scoring of nuclear parafibromin alone. [ABSTRACT FROM AUTHOR]

The identification of parathyroid carcinomas is based upon histopathological criteria in which an invasive growth pattern or distant metastasis is demonstrated. A dilemma arises when tumours present with atypical histopathological features but lack direct evidence of malignancy. Recently, reduced expression or loss of the tumour suppressor proteins parafibromin and adenomatous polyposis coli (APC) has been associated with parathyroid malignancy. We report results from APC and parafibromin expression analyses by immunohistochemistry and Western blot in five cases of atypical adenoma, a single case of carcinoma and 54 adenomas without atypical features. Complete loss of APC immunoreactivity and reduced expression of parafibromin was evident in two of the atypical adenomas and in the parathyroid carcinoma. By contrast, all adenomas displayed APC expression, including two cases with hyperparathyroidism 2 gene ( HRPT2) mutations and loss of parafibromin expression. We conclude that loss of APC is a frequent molecular event in atypical adenomas and carcinomas, but not in adenomas. Following verification in an independent material, APC could become a valuable tool when assessing parathyroid tumours in the clinical setting. Furthermore, the molecular resemblance of atypical adenomas with carcinoma concerning parafibromin and APC expression indicates that atypical adenomas should be subjects to watchful follow-up. [ABSTRACT FROM AUTHOR]

Abstract: The risk for parathyroid carcinoma is high in those with the HPT-JT syndrome. Parafibromin is a protein derived from HRPT2 gene and its inactivation has been coupled to familial form of parathyroid malignancy. We previously identified altered transcripts resulting from splice site mutation of the HRPT2 gene in a family with this syndrome. In the present work, we investigated the stability of the altered HRPT2 transcripts and translation products produced in the HPT-JT syndrome. We quantified the differentially expressed HRPT2 mRNAs using real-time RT-PCR and developed a novel monoclonal parafibromin antibody to study the expression of parafibromin in the HPT-JT syndrome. The relative quantification ratios of the wild type HRPT2 mRNA, 23 bp deleted HRPT2 mRNA, and 70 bp deleted HRPT2 mRNA in the HPT-JT syndrome were 0.68, 0.17 and 0.15, respectively. But endogenous parafibromin expression was not detectable in the HPT-JT syndrome carcinoma. The altered HRPT2 mRNAs resulting from the splice site mutation in the HPT-JT syndrome were stable, but their parafibromin translation products from the HPT-JT syndrome carcinoma were probably degraded rapidly. Additional studies that aim to fully characterize the consequences of altered HRPT2 mRNAs in HPT-JT syndrome are required to explore these possibilities. [Copyright &y& Elsevier]

Hyperparathyroidism–jaw tumor syndrome (HPT–JT) is a rare autosomal disease caused by inactivating germ-line mutations of HRPT2 gene, with subsequent loss of Parafibromin expression. It is characterized by familial HPT, ossifying jaw tumors, and other associated neoplasms. Clinical, histopathological, and genetic features of three large Italian unrelated HPT–JT kindred were assessed. Three different germ-line HRPT2 inactivating mutations were identified. Seventeen affected members and six healthy mutation carriers were found. HPT was diagnosed in virtually all affected patients, at a median age of 36.3 years (range 11–71). In all cases, a single parathyroid involvement was found at surgery, although a metachronous multiglandular involvement causing recurrence after selective parathyroidectomy occurred in 17.6% of cases, after a mean disease-free interval of 13.7 years (range 5–27). Parathyroid carcinoma, atypical parathyroid adenoma, and jaw tumor occurred in one case; uterine involvement in 61.5% of women; other associated neoplasms were thyroid carcinoma (two cases) and renal and colon carcinoma (one case). Immunohistochemistry confirmed the loss of Parafibromin as the distinctive feature of the disease both in parathyroid and uterine tumors. HPT–JT has a frequent single-gland parathyroid involvement and a relatively increased risk of parathyroid carcinoma. The penetrance of the disease is high but incomplete. Regardless of the denomination of the syndrome, jaw tumors occur rarely, while uterine involvement is frequently present. Selective parathyroidectomy may be an effective strategy, but a prolonged follow-up is required because of the risk of recurrences and malignancies. A systematic investigation is also required because of associated malignancies. [ABSTRACT FROM AUTHOR]

Parathyroid neoplasms encompass a spectrum of proliferative lesions that include adenomas, atypical adenomas, and carcinomas. While the diagnosis of adenomas is usually straightforward, parathyroid carcinomas (PTCAs) often present considerable diagnostic challenges. Fibrosis and mitotic activity are common in PTCAs, but these features are not specific for malignancy. An unequivocal diagnosis of PTCA should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases. Atypical adenomas include those tumors that share some of the features of PTCA but lack evidence of invasive growth. A variety of genetic abnormalities, including HRPT2 mutations, occur in PTCAs. Mutations of the HRPT2 gene, which encodes parafibromin, are responsible for the development of the hyperparathyroidism–jaw tumor syndrome and have also been implicated in the development of a high proportion of sporadic PTCAs. Correlative immunohistochemical studies have revealed nuclear parafibromin immunoreactivity in adenomas but absence or partial loss of staining in PTCAs. While parafibromin immunohistochemistry represents an important step in the ability to diagnose PTCA, additional studies will be required to test the validity of this approach and to determine the roles of other genes in the development of these tumors. [ABSTRACT FROM AUTHOR]

Parafibromin is a tumor suppressor protein encoded by HRPT2, a gene recently implicated in the hereditary hyperparathyroidismjaw tumor syndrome, parathyroid cancer, and a subset of kindreds with familial isolated hyperparathyroidism. Human parafibromin binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex. The physiologic targets of parafibromin and the mechanism by which its loss of function can lead to neoplastic transformation are poorly understood. We show here that RNA interference with the expression of parafibromin or Paf 1 stimulates cell proliferation and increases levels of the c-myc protooncogene product, a DNA-binding protein and established regulator of cell growth. This effect results from both c-myc protein stabilization and activation of the c-myc promoter, without alleviation of the c-myc transcriptional pause. Chromatin immunoprecipitation demonstrates the occupancy of the c-myc promoter by parafibromin and other PAF1 complex subunits in native cells. Knockdown of c-myc blocks the proliferative effect of RNA interference with parafibromin or Paf 1 expression. These experiments provide a previously uncharacterized mechanism for the antiproliferative action of the parafibromin tumor suppressor protein resulting from PAF1 complex-mediated inhibition of the c-myc proto-oncogene. [ABSTRACT FROM AUTHOR]

Parathyroid carcinoma is an uncommon cause of primary hyperparathyroidism (PHPT) and is usually associated with more severe clinical manifestations than its much more common benign counterpart, the parathyroid adenomas. The histopathological distinction between benign and malignant parathyroid tumors is difficult. Currently, pathological diagnosis of parathyroid carcinoma is restricted to lesions showing unequivocal growth, as evidenced by perineural invasion, full-thickness capsular invasion with growth into adjacent tissues, or metastasis. Major advances in the molecular pathogenesis of parathyroid carcinoma have been made by the cloning of the HRPT2 gene, which encodes parafibromin, a 531-amino acid putative tumor-suppressor protein. Germline mutations of HRPT2 confer susceptibility to the hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant syndrome with high but incomplete penetrance. Somatic inactivating mutations of the HRPT2 gene have been reported in the majority of apparently sporadic parathyroid carcinomas but, unexpectedly, germline HRPT2 mutation have been found in up to 30% of these patients. Several studies have been performed to evaluate whether parafibromin immunostaining might have some diagnostic utility. Loss of parafibromin immunoreactivity has been found in the majority of parathyroid carcinomas, in 50% of equivocal carcinomas and, very rarely, in benign adenomas. On the other hand, with the exception of HPT-JT-related tumors, loss of parafibromin associated with HRPT2 mutations strongly predicts parathyroid malignancy. In clinical practice, parafibromin immunostaining and HRPT2 gene analysis could be particularly useful in the subset of parathyroid tumors with equivocal histology. [ABSTRACT FROM AUTHOR]

Parafibromin (PF) is a 531-amino acid protein encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal-dominant hyperparathyroidism-jaw tumor familial cancer syndrome and sporadic parathyroid carcinoma. To investigate effects of PF's overexpression on cell proliferation, we performed assays in four different cell lines. The transient overexpression of PF inhibited cell growth in HEK293 and NIH3T3 cells, but enhanced cell growth in the SV40 large T antigen-expressing cell lines such as 293FT and COS7 cells. In 293FT cells, PF was found to interact with SV40 large T antigen and its overexpression promoted entry into the S phase, implying that the interaction enhanced progression through the cell cycle. The tumor suppressor protein PF acts as a positive regulator of cell growth similar to an oncoprotein in the presence of SV40 large T antigen.Oncogene (2007) 26, 6176–6183; doi:10.1038/sj.onc.1210445; published online 2 April 2007 [ABSTRACT FROM AUTHOR]

Parafibromin is a protein encoded by the HRPT2 oncosuppressor gene, whose mutation causes the hyperparathyroidism–jaw tumour syndrome, characterized by the occurrence of parathyroid adenoma or carcinoma, fibro-osseous jaw tumours, and renal neoplastic and non-neoplastic abnormalities. Non-morphological techniques, such as Northern and Western blotting and reverse transcriptase-PCR, indicate that parafibromin is ubiquitously expressed, but extensive immunohistochemical studies have not been performed. To increase our knowledge of the distribution and patterns of expression of parafibromin, we examined its expression and location in many different mouse and human organs by immunohistochemistry. There were no substantial differences in parafibromin expression between mouse and human. We found widespread expression of parafibromin, except in connective tissue, smooth muscle, endothelium and some other types of epithelia (colonic, urinary, tubaric, uterine, thyroid). Heterogeneity of positivity intensity and subcellular location (nuclear, nucleocytoplasmic, cytoplasmic) was found between tissues and cell types, suggesting differential functional involvement of parafibromin. Moreover, higher parafibromin expression was found in cell types, such as hepatocytes, cells of the base of gastric glands, renal cortex tubules and the pars intermedia of the hypophysis, which are characterized by different proliferative capacity, thus indicating that the cellular function of parafibromin may not be reduced only to its anti-proliferative effect. [ABSTRACT FROM AUTHOR]

Abstract: The HRPT2 (hereditary hyperparathyroidism type 2) tumor suppressor gene encodes a ubiquitously expressed 531 amino acid protein termed parafibromin. Inactivation of parafibromin predisposes one to the development of HPT-JT syndrome. To date, the role of parafibromin in tumorigenesis is largely unknown. Here, we report that parafibromin is a nuclear protein that possesses anti-proliferative properties. We show that overexpression of parafibromin inhibits colony formation and cellular proliferation, and induces cell cycle arrest in the G1 phase. Moreover, HPT-JT syndrome-derived mutations in HRPT2 behave in a dominant-negative manner by abolishing the ability of parafibromin to suppress cell proliferation. These findings suggest that parafibromin has a critical role in cell growth, and mutations in HRPT2 can directly inhibit this role. [Copyright &y& Elsevier]

Parafibromin is a putative tumor suppressor encoded by HRPT2, mutations in which have been implicated in the familial tumor syndrome hyperparathyroidism jaw tumor syndrome (HPT-JT), and sporadic parathyroid carcinoma. Recently, parafibromin has been shown to be an accessory factor for RNA polymerase II as part of the human Paf1 complex, suggesting, as has been shown for its yeast homologue (Cdc73), that it may have a role as an important regulator of transcription. Parafibromin has also been shown to interact with a histone methyltransferase complex that methylates histone H3 and to inhibit proliferation when overexpressed in mammalian cell lines. Despite these findings, the cellular localization of parafibromin has been controversial, with reports of both nuclear and nucleocytoplasmic localization. We have expressed wild-type and mutant parafibromin tagged with enhanced green fluorescent protein and have identified a functional bipartite nuclear localization signal (NLS) at residues 125–139 (nucleotides 373–417), KRAADEVLAEAKKPR, that is evolutionarily conserved and critical for the nuclear localization of parafibromin. We have also shown that the C-terminal arm of this bipartite NLS plays the primary role in nuclear localization. In support of these findings, specific HRPT2 mutations identified in HPT-JT or sporadic parathyroid carcinoma predicted to truncate parafibromin upstream of or within this NLS disrupt nuclear localization.Oncogene (2005) 24, 6241–6248. doi:10.1038/sj.onc.1208778; published online 22 August 2005 [ABSTRACT FROM AUTHOR]

Marx SJ, Stratakis CA (National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA). Multiple Endocrine Neoplasia– Introduction (Minisymposium).J Intern Med2005;257:2–5.Each multiple endocrine neoplasia (MEN) syndrome expresses striking features of hormone oversecretion from its own characteristic group of tissues. Additional expressions include non-hormonal tumours in each MEN syndrome and selected cancers in some syndromes. The complexity of its stereotyped features results in difficult management issues that often justify cooperation across multiple specialties. MEN syndromes, though rare, have long received intense study as models for more common diseases. The syndromal nature often with a large pedigree has promoted recent discovery of the main gene that differs for each of the six MEN syndromes. Each mutant gene has been introduced into clinical decision-making and into further clarification of tumorigenesis. This mini-symposium is related to the 9th International Workshop on Multiple Endocrine Neoplasia in June 2004; it consists of six manuscripts. They report new developments in clinical practices and in basic understandings about this rapidly advancing field. [ABSTRACT FROM AUTHOR]

Amongst hyperparathyroidism-related syndromes, hyperparathyroidism-jaw tumour syndrome is one of the least common and relatively unknown but its clinical and genetic aspects are not less interesting or important. With the recent identification of its genes, we can now better characterize the disease, both clinically and genetically, which will certainly impact the field of endocrinology and oncology. In this article, we review the clinico-pathological features and genetic basis of this syndrome with the hope that it will create awareness and interest in this disease amongst clinicians and basic scientists. [ABSTRACT FROM AUTHOR]

An important emerging role of the surgical pathologist besides the traditional tasks of establishment of the diagnosis and documentation of prognostic and predictive factors, is to recognize the possibility of a hereditary condition in cases where the histology is suggestive for a familial cancer syndrome. In recent years, the knowledge regarding all of the above roles, including the role of recognition of familial cancer, has particularly expanded in renal neoplasms with the close scrutiny to morphology, molecular correlates and clinical features of the different sub-types of renal cell carcinoma. Awareness of these clinically distinctive sub-types and their associated histologic clues will prompt the pathologist for further immunohistochemical or molecular work up, to look for clinical information to support the suspected diagnosis of familial cancer, to alert managing physician/s to look for stigmata of history of familial cancer, which will permit triaging patients and their families for appropriate genetic counseling. This review provides a comprehensive review of the known sub-types of renal cell carcinoma that have a predilection to occur in the setting of hereditary disease; examples include renal cancers occurring in the background of von Hippel Lindau disease, hereditary leiomyomatosis and renal cell carcinoma syndrome, tuberous sclerosis, Birt Hogg Dube syndrome and succinate dehydrogenase deficiency. Herein we focus on diagnostic clues for renal tumors occurring in a non-pediatric setting that should prompt their correct recognition and reiterate the importance of the correct diagnosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Wilms tumor 1 gene (WT1) can either repress or induce the expression of genes. Inconsistent with its tumor suppressor role, elevated WT1 levels have been observed in leukemia and solid tumors. WT1 has also been suggested to act as an oncogene by inducing the expression of MYC and BCL-2. However, these are only the correlational studies, and no functional study has been performed to date. Consistent with its tumor suppressor role, CDC73 binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex and causes transcriptional repression of oncogenes MYC and CCND1. It also represses β-catenin-mediated transcription. Based on the reduced level of CDC73 in oral squamous cell carcinoma (OSCC) samples in the absence of loss-of-heterozygosity, promoter methylation, and mutations, we speculated that an inhibitory transcription factor is regulating its expression. The bioinformatics analysis predicted WT1 as an inhibitory transcription factor to regulate the CDC73 level. Our results showed that overexpression of WT1 decreased CDC73 levels and promoted proliferation of OSCC cells. ChIP and EMSA results demonstrated binding of WT1 to the CDC73 promoter. The 5-azacytidine treatment of OSCC cells led to an up-regulation of WT1 with a concomitant down-regulation of CDC73, further suggesting regulation of CDC73 by WT1. Exogenous CDC73 attenuated the protumorigenic activity of WT1 by apoptosis induction. An inverse correlation between expression levels of CDC73 and WT1 was observed in OSCC samples. These observations indicated that WT1 functions as an oncogene by repressing the expression of CDC73 in OSCC. We suggest that targeting WT1 could be a therapeutic strategy for cancer, including OSCC.

This study reported a family with primary hyperparathyroidism due to parathyroid carcinoma and investigated the pathological and genetic features of family members. Three members of the family had clinical manifestation of primary hyperparathyroidism and tumors in the neck. All three patients underwent parathyroidectomy, thyroidectomy and level-VI neck dissection and were definitively diagnosed based on pathology. The index case was a patient that was found to have parathyroid carcinoma on the right side and parathyroid adenoma on the left side. The other two patients had local tumor recurrence and metastasis to distant organs. A germline mutation in the HRPT2 gene (Arg91Pro) was identified in all of the patients in this family. Study of the literature indicated that this is the first report of familial parathyroid carcinomas with an HRPT2 gene missense mutation. Results also indicated that HRPT2 may play an important role in the development of parathyroid carcinoma.