Characterization of renal cell carcinoma-associated constitutional chromosome abnormalities by genome sequencing.

Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt-Hogg-Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC-associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC-associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation-associated RCC, and (d) demonstrate the utility of GS for investigating such cases.

Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions.

Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.

Papillary Renal Cell Carcinoma With Osteosarcomatous Heterologous Differentiation: A Case Report With Molecular Genetic Analysis and Review of the Literature.

Sarcomatoid differentiation can occur in all subtypes of renal cell carcinoma (RCC). In rare cases, heterologous differentiation has been described. We present a case of heterologous osteosarcomatous differentiation in association with sarcomatoid papillary RCC including an analysis of chromosomal copy number alteration. This is the first case to identify heterologous differentiation in association with papillary RCC. The patient was a 70-year-old man who had a mass in the right kidney. Speckled calcification was seen on computed tomography scan. Histological assessment demonstrated papillary RCC merging with areas of sarcomatoid change and malignant bone formation simulating osteosarcoma. Cytogenetic evaluation demonstrated additional copies of chromosome 7 in both epithelial and osteosarcomatous components. A literature review identified 33 previous cases of heterologous differentiation in association with RCC. Of the 14 cases that reported an epithelial subtype, 13 cases were reported to be chromophobe RCC and 1 case was reported to be clear cell RCC.