Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer

Koski, Taru A.; Lehtonen, Heli; Jee, Kowan Ja; Ninomiya, Shinsuke; Joosse, Simon A.; Vahteristo, Pia; Kiuru, Maija; Karhu, Auli; Sammalkorpi, Heli; Vanharanta, Sakari; Lehtonen, Rainer; Edgren, Henrik; Nederlof, Petra M.; Hietala, Marja; Aittomäki, Kristiina; Herva, Riitta; Knuutila, Sakari; Aaltonen, Lauri A.; Launonen, Virpi

doi:10.1002/gcc.20663

Cited by 28 publications

(9 citation statements)

References 31 publications

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“…MET overexpression is by far more frequent than mutations in human cancers (http://www.vai.org/met). Notably, MET mutations were not detected in a series of renal cell cancers associated with HLRCC, while the whole chromosome 7 gain including MET at 7q31.2 was found in 27% of these cases (50). MET overexpression is associated with amplification in a number of cancers, but overexpression is also attained by mechanisms other than gene amplification.…”

Section: Discussionmentioning

confidence: 93%

Fumarase tumor suppressor gene andMEToncogene cooperate in upholding transformation and tumorigenesis

et al. 2010

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Loss of the fumarate hydratase (FH) tumor suppressor gene results in the development of benign tumors that rarely, but regrettably, progress to very aggressive cancers. Using mouse embryo fibroblasts (MEFs) to model transformation, we found that fh knockdown results in increased expression of the met oncogene-encoded tyrosine kinase receptor through hypoxia-inducible factor (hif) stabilization. MET-increased expression was alone able to stabilize hif, thus establishing a feed forward loop that might enforce tumor progression. The fh-defective MEFs showed increased motility and protection from apoptosis. Motility, but not survival, relied on hif-1alpha and was greatly enhanced by MET ligand hepatocyte growth factor. Met cooperated with a weakly oncogenic ras in making MEFs transformed and tumorigenic, as shown by in vitro and in vivo assays. Loss of fh was not equally effective by itself but enhanced the transformed and tumorigenic phenotype induced by ras and MET. Consistently, the rescue of fumarase expression abrogated the motogenic and transformed phenotype of fh-defective MEFs. In conclusion, the data suggest that the progression of tumors where FH is lost might be boosted by activation of the MET oncogene, which is able to drive cell-autonomous tumor progression and is a strong candidate for targeted therapy.

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Section: Discussionmentioning

confidence: 93%

Fumarase tumor suppressor gene andMEToncogene cooperate in upholding transformation and tumorigenesis

et al. 2010

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“…(23-26) It remains unknown whether HLRCC renal tumors could consist exclusively or almost exclusively of a tubulocystic element, although most of the tubulocystic carcinomas described are pure, well-circumscribed tumors with overall good prognosis. (27) In an array comparative genomic hybridization (aCGH) study of renal tumors associated with HLRCC(28), about 30-40% HLRCC tumors appeared to harbor chromosomal 7 or 17 gains, suggesting that trisomy 7 or 17 by FISH is not a reliable marker to separate HLRCC renal cancer from sporadic papillary RCC or tubulocystic carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome–associated Renal Cancer

Chen¹,

Brannon²,

Toubaji³

et al. 2014

American Journal of Surgical Pathology

225

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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase (FH) gene confer an increased risk of cutaneous and uterine leiomyomas as well as renal cancer. HLRCC-associated renal cancer is highly aggressive, and frequently presents as a solitary mass. We reviewed the clinicopathologic features of 9 patients with renal tumors presenting as sporadic cases, but who were later proven to have FH germline mutations. Histologically, all tumors showed mixed architectural patterns, with papillary as the dominant pattern in only 3 cases. Besides papillary, tubular, tubulopapillary, solid and cystic elements, 6 of 9 tumors contained collecting duct carcinoma-like areas with infiltrating tubules, nests or individual cells surrounded by desmoplastic stroma. Prominent tubulocystic carcinoma-like component and sarcomatoid differentiation were identified. While all tumors exhibited the proposed hallmark of HLRCC (large eosinophilic nucleolus surrounded by a clear halo), this feature was often not uniformly present throughout the tumor. Prior studies have shown that high level of fumarate accumulated in HLRCC tumor cells causes aberrant succination of cellular proteins by forming a stable chemical modification, S-(2-succino)-cysteine (2SC), which can be detected by immunohistochemistry. We thus explored the utility of detecting 2SC by immunohistochemistry in the differential diagnosis of HLRCC tumors and other high-grade renal tumors, and investigated the correlation between 2SC staining and FH molecular alterations. All confirmed HLRCC tumors demonstrated diffuse and strong nuclear and cytoplasmic 2SC staining, while all clear cell (184/184, 100%), most high-grade unclassified RCC (93/97, 96%) and the large majority of type 2 papillary (35/45, 78%) cases showed no 2SC immunoreactivity. A subset of papillary (22%) and rare unclassified (4%) tumors showed patchy or diffuse cytoplasmic staining without nuclear labeling, unlike the pattern seen with confirmed HLRCC tumors. Sequencing revealed no germline or somatic FH alterations in 14 tumors that either exhibited only cytoplasmic 2SC staining (n=5) or were negative for 2SC (n=9), despite their HLRCC-like morphologic features. Our results emphasize the pivotal role of pathologic examination in the diagnosis of HLRCC patients, and indicate immunohistochemical detection of 2SC as a useful ancillary tool in the differentiation of HLRCC renal tumors from other high-grade renal cell carcinomas.

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“…Genomic alterations characteristic of the HLRCC renal tumors include loss of chromosome 1q, related to loss of the FH wildtype allele in tumors [41]. Genomic profiling of RCCs by array CGH has shown frequent changes that include gain of chromosomes 2, 7, and 17 and loss of 13q12.3-q21.1, 14q, 18, and X [44]. A possible implication of the alterations in tumorigenesis has not been assessed.…”

Section: Renal Tumorsmentioning

confidence: 96%

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

2011

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Hereditary leiomyomatosis and renal cell cancer (HLRCC, also known as multiple cutaneous and uterine leiomyomatosis, MCUL) is a highly penetrant autosomal dominant tumor predisposition syndrome characterized by benign leiomyomas of the skin and the uterus. Renal cell carcinomas, occurring in a subset of the HLRCC families, are exceptionally aggressive. Therefore careful, frequent surveillance strategies are recommended. Association of malignant smooth-muscle tumors, leiomyosarcomas, with HLRCC has been observed but the risk appears to be smaller than initially estimated. To date inactivating heterozygous mutations in the fumarate hydratase (FH, fumarase) gene, predisposing to HLRCC, have been found in approximately 180 families worldwide. The most extensively studied hypothesis on molecular mechanisms of HLRCC tumorigenesis is activation of the hypoxia pathway due to aberrant stabilization of the HIF1 transcription factor. HIF1 regulates transcription of genes relevant for vascularization, glucose transport and glycolysis, processes that facilitate tumor growth. However, additional mechanisms underlying tumor formation are likely to exist.

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Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer

Cited by 28 publications

References 31 publications

Fumarase tumor suppressor gene andMEToncogene cooperate in upholding transformation and tumorigenesis

Fumarase tumor suppressor gene andMEToncogene cooperate in upholding transformation and tumorigenesis

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome–associated Renal Cancer

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

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