Hereditary kidney cancer

Linehan, W. Marston; Pinto, Peter A.; Bratslavsky, Gennady; Pfaffenroth, Elizabeth Cartwright; Merino, María J.; Vocke, Cathy D.; Toro, Jorge R.; Bottaro, Donald P.; Neckers, Len; Schmidt, Laura S.; Srinivasan, Ramaprasad

doi:10.1002/cncr.24230

Cited by 94 publications

(21 citation statements)

References 114 publications

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“…In an analogous strategy, efforts are currently underway to quantitatively evaluate the risk of cancers other than germ cell tumors to see if the spectrum of syndrome-related malignancies might be broader than expected. We are also conducting a blinded central pathology review of both familial and sporadic TGCTs by expert germ cell tumor pathologists in the hope of identifying subtle differences in these histologically complex tumors that might provide a guide to sub-group homogeneity in a manner similar to that applied so successfully in the hereditary renal cancer syndromes (Linehan et al 2009). …”

Section: What Is the Ftgct Phenotype?mentioning

confidence: 99%

Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype

Greene¹,

Kratz²,

Phuong³

et al. 2010

Endocrine-Related Cancer

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Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2–3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.

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Section: What Is the Ftgct Phenotype?mentioning

confidence: 99%

Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype

Greene¹,

Kratz²,

Phuong³

et al. 2010

Endocrine-Related Cancer

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“…Despite the discovery of other RCC predisposing genes mutated in the germline, 16 no other genes were found to be frequently implicated in sporadic ccRCC until the advent of massively parallel sequencing technologies. Technological developments have enabled the discovery of a multitude of genes somatically mutated in ccRCC, including PBRM1 (Polybromo 1), BAP1 (BRCA1-associated protein 1) and SETD2 (SET domain-containing protein 2).…”

Section: Introductionmentioning

confidence: 99%

PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma

Brugarolas

2013

The Cancer Journal

104

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Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, one gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial RCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes have been identified. Most genes are mutated at low frequencies, but three genes are mutated in >10% of ccRCC, PBRM1 (mutated in ~50%), BAP1 (~15%) and SETD2 (~15%). Like VHL, all 3 genes are two-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50 Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in over 90% of ccRCC. We discovered that PBRM1 mutations tend to anti-correlate with BAP1 mutations in ccRCC, and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically.

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“…BHD patients are each likely to have various types of RCC [13], especially those with tumors with composite oncocytoma or chromophobe RCC histology [14]; these pathologies include the known familial hereditary RCCs, such as von Hippel-Lindau (VHL) syndrome, BHD syndrome, hereditary papillary renal cell carcinoma (HPRCC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and tuberous sclerosis complex (TSC). Pavlovich et al [10] summarized clinical data of 124 BHD patients with 84 resected renal tumors, of which 56 (67%) were hybrid oncocytic tumors, 19 (23%) were chromophobe RCC, 6 (7%) were clear-cell RCC, and 3 (4%) were renal oncocytoma.…”

Section: Discussionmentioning

confidence: 99%

Novel germline mutations in FLCN gene identified in two Chinese patients with Birt–Hogg–Dubé syndrome

Ning

et al. 2017

Chin J Cancer

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Birt–Hogg–Dubé (BHD) syndrome, a hereditary renal cancer syndrome caused by mutations in the folliculin (FLCN) gene, is characterized by the presence of fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cell carcinoma (RCC). Few BHD syndrome cases have been reported in Asian countries, and cutaneous presentations are relatively rare in Asian patients. Asian BHD patients may be misdiagnosed due to their atypical manifestations. Here, we report two Chinese BHD patients with novel FLCN mutations (c.946-947delAG in exon 9 and c.770-772delCCT in exon 7). Both of them had RCC and spontaneous pneumothorax without fibrofolliculomas. In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pulmonary cysts (pneumothorax).

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Hereditary kidney cancer

Abstract: Kidney cancer is not a single disease; it is comprised of several different types of cancer, each with a dif-

Cited by 94 publications

References 114 publications

Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype

Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype

PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma

Novel germline mutations in FLCN gene identified in two Chinese patients with Birt–Hogg–Dubé syndrome

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