Origin of renal cell carcinomas.
ABSTRACT Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the "two hits" of Knudson's hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition.
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ABSTRACT: In this study, 105 non-papillary renal cell carcinomas (RCCs) have been examined for allelic loss at the chromosome 8p12-21.1, 9p21, and 14q24.2-qter regions, each by two highly polymorphic microsatellites. Loss of heterozygosity (LOH) was detected at both chromosome 8p and 9p in 33 per cent of the cases and at chromosome 14q in 45 per cent of the tumours. A correlation of variables such as size, grade, and stage of tumours with these specific genetic alterations showed that loss of chromosomes 8p and 9p, and especially loss of chromosome 14q regions, is significantly associated with a higher grade of tumour and the combined LOH at these chromosomal sites with advanced tumour stage. These genetic alterations did not show any correlation with the size of non-papillary RCCs. This study suggests that genetic markers at the above-mentioned chromosomal sites can predict the clinical outcome of non-papillary RCCs.The Journal of Pathology 11/1997; 183(2):151-5. · 7.59 Impact Factor
Article: Molecular genetics of kidney cancer.[show abstract] [hide abstract]
ABSTRACT: Tumorigenesis is a multistep process of genetic and epigenetic changes that occur in an orderly fashion The order of these changes may navigate through different steps in cancers arising from different organs/tissues. It is likely though that the final outcome is the sequential deregulation of a few key pathways of normal cell growth, namely: inactivation of tumor suppressor genes; activation of oncogenes; evasion of apoptotic cell program; and ultimately induction of angiogenesis and metastasis.’ Entry points to these genetic alterations were discovered by cloning genes disrupted by tumor-associated chromosomal translocations, harbored in cancer-associated homozygous deletions or underlying familial cancer syndromes.Cancer treatment and research 02/2003; 116:3-27.
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ABSTRACT: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant genodermatosis characterized by the development of small dome-shaped papules on the face, neck, and upper trunk (fibrofolliculomas). In addition to these benign hair follicle tumors, BHD confers an increased risk of renal neoplasia and spontaneous pneumothorax. To date, there has been no systematic pathologic analysis of the renal tumors associated with this syndrome. We reviewed 130 solid renal tumors resected from 30 patients with BHD in 19 different families. Preoperative computed tomography scans demonstrated a mean of 5.3 tumors per patient (range 1-28 tumors), the largest tumors averaging 5.7 cm in diameter (+/- 3.4 cm, range 1.2-15 cm). Multiple and bilateral tumors were noted at an early age (mean 50.7 years). The resected tumors consisted predominantly of chromophobe renal cell carcinomas (44 of 130, 34%) or of hybrid oncocytic neoplasms that had areas reminiscent of chromophobe renal cell carcinoma and oncocytoma (65 of 130, 50%). Twelve clear cell (conventional) renal carcinomas (12 of 130, 9%) were diagnosed in nine patients. These tumors were on average larger (4.7 +/- 4.2 cm) than the chromophobe (3.0 +/- 2.5 cm) and hybrid tumors (2.2 +/- 2.4 cm). Microscopic oncocytosis was found in the renal parenchyma of most patients, including the parenchyma of five patients with evidence of clear cell renal cell carcinoma. Our findings suggest that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear cell renal cell carcinomas in patients with BHD syndrome. Recognition by the pathologist of the unusual renal tumors associated with BHD may assist in the clinical diagnosis of the syndrome.American Journal of Surgical Pathology 01/2003; 26(12):1542-52. · 4.87 Impact Factor