Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer.
ABSTRACT Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome with cutaneous and uterine leiomyomatosis as well as renal cell cancer (RCC) as its clinical manifestations. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (fumarase) gene. In this study, we used array comparative genomic hybridization to identify the specific copy number changes characterizing the HLRCC-associated RCCs. The study material comprised formalin-fixed paraffin-embedded renal tumors obtained from Finnish patients with HLRCC. All 11 investigated tumors displayed the papillary type 2 histopathology typical for HLRCC renal tumors. The most frequent copy number changes detected in at least 3/11 (27%) of the tumors were gains in chromosomes 2, 7, and 17, and losses in 13q12.3-q21.1, 14, 18, and X. These findings provide genetic evidence for a distinct copy number profile in HLRCC renal tumors compared with sporadic RCC tumors of the same histopathological subtype, and delineate chromosomal regions that associate with this very aggressive form of RCC.
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ABSTRACT: We evaluated clinical characteristics, patient outcome (mean follow-up, 47 months), and cytogenetic abnormalities in the largest as yet reported cytogenetic series of 47 primary and 11 secondary papillary renal cell carcinomas for differences between the recently proposed type 1 and type 2 subtypes. Secondary tumors were more often of type 2 morphology (P = 0.02), whereas primary type 2 tumors were associated with higher clinical stage (P = 0.001) and worse patient outcome (P = 0.02). Although both subtypes had at least one of the primary chromosomal gains at 17q, 7, and 16q, type 2 tumors had moderately lower frequencies of primary gains at 17p (61 versus 94%; P = 0.007) and 17q (72 versus 97%; P = 0.02). On the other hand, type 2 tumors overall had more chromosomal alterations than type 1 tumors (P = 0.01), particularly gains of 1q (28 versus 3%; P = 0.02) and losses of 8p (33 versus 0%; P = 0.001), 11 (28 versus 3%; P = 0.02), and 18 (44 versus 9%; P = 0.01). Hierarchical clustering suggested cytogenetic patterns common but not restricted to type 2 morphology, one characterized by multiple additional gains, and another predominantly showing additional losses. These findings provide genetic evidence that type 1 and type 2 tumors arise from common cytogenetic pathways and that type 2 tumors evolve from type 1 tumors. Independently of type, losses of 9p were statistically correlated with advanced disease (P = 0.0008) and may serve as a potential adverse prognostic marker in papillary renal cell carcinomas.Cancer Research 11/2003; 63(19):6200-5. · 8.65 Impact Factor
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ABSTRACT: The 18q chromosome arm is frequently lost in advanced head and neck squamous cell carcinoma. Twenty-four microsatellite markers located on chromosome 18q were genotyped in 145 primary tumors and 10 cell lines in order to identify putative tumor suppressor genes implicated in tumor progression. Two different minimal common regions of loss (MCRL) were identified at 18q22 and 18q23 respectively. To refine and delineate boundaries of an homozygous deletion found in one cell line, 44 extra markers located at 18q22 were analysed and the homozygous deletion was precisely defined within a critical region of 4.9 Mb. Four known genes (CDH7, CDH19, DNAM-1, FLJ23594) located in this critical region and two EST clusters (Hs.96900, Hs.98628) were selected for further investigations. For these six genes, genomic structures were established, somatic mutations were screened in 20 HNSCC and 10 cell lines and transcription levels were determined in eight cell lines. No somatic mutations were found in any of the candidate genes analysed (57 coding exons). However, differential transcription levels were observed for CDH19 and Hs.96900 in head and neck cancer cell lines supporting their putative involvement through down regulation mechanisms in head and neck cancer progression.Oncogene 08/2002; 21(32):5016-23. · 7.36 Impact Factor
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ABSTRACT: Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis1, 2, 3. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3−q43 (refs 4−6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency7, 8, 9, 10, 11, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor12, 13, 14.Nature Genetics 05/2002; · 35.21 Impact Factor