Genetic Testing in Urinary Tract Cancers

Gayun Chan-Smutko

INTRODUCTION

Cancers of the urinary tract include renal cell carcinoma (RCC) and transitional cell carcinoma, or urothelial carcinoma (UC). About 64,770 cases of invasive cancer of the kidney and renal pelvis, 74,510 cases of urinary bladder cancer, and 2,860 cases of cancer of the ureter and other urinary organs are expected to be diagnosed in men and women in the United States in 2012.¹ The lifetime risk of cancer of the kidney and renal pelvis is 1.6%, with an average age at diagnosis (based on statistics from 2005 to 2009) of 64 years.² A family history of RCC is associated with a 2.2- to 2.8-fold increased risk for developing RCC.³ Most cases of RCC are sporadic, and approximately 4% are due to a hereditary susceptibility.

RCC is a heterogeneous disease, which has been divided into the following subtypes based on the World Health Organization 2004 classification system: Clear cell (80%), papillary types 1 and 2 (10%), chromophobe (5%), collecting duct (1%), and RCC unclassified (4% to 6%). Additional rarer types that collectively account for <2% of RCCs have been described as well.⁴ The molecular pathways driving tumorigenesis in hereditary syndromes such as von Hippel-Lindau (VHL) disease, Birt-Hogg-Dubé (BHD) syndrome, hereditary leiomyomatosis and RCC, and hereditary papillary renal cell carcinoma (HPRCC) have provided greater insight into the molecular mechanisms behind the four major subtypes of RCC. This understanding has led to targeted therapies aimed at specific molecular pathways such as the hypoxia-inducible factor (HIF) pathway. This review is devoted primarily to the discussion of renal neoplasms in the adult population and their associated hereditary syndromes (Table 40.1). Genetic testing for susceptibility to urothelial cancers of the upper urinary tract is also presented.

GENETIC SUSCEPTIBILITY TO RENAL CELL CARCINOMA

von Hippel-Lindau Disease

VHL disease is an autosomal dominant condition that affects approximately 1 in 36,000 live births worldwide. The VHL gene is located on the short arm of chromosome 3 (3p25) and is the only known susceptibility locus associated with the condition. It is a well-studied tumor suppressor gene that demonstrates loss of heterozygosity in RCCs of patients with VHL disease and sporadic clear cell RCC as well.

VHL disease is a multisystem condition, and an affected individual is at risk to develop any of the following lesions: (1) hemangioblastoma of the cerebellum, spine, or retina; (2) papillary cystadenoma of the epididymis, the adnexal organs, or the endolymphatic sac; (3) adrenal pheochromocytoma and occasionally extra-adrenal paraganglioma; (4) pancreatic cysts, serous cystadenomas, and neuroendocrine tumors (NET); and (5) multiple and/or bilateral RCC and cysts.

Although the penetrance of VHL disease is 100%, where individuals will develop at least one associated lesion by their sixth decade of life, the expressivity is highly variable even among individuals sharing the same gene mutation. The disease is phenotypically categorized into type 1 and type 2 based on risk for developing pheochromocytoma, with the latter further divided into three subtypes (2A, 2B, and 2C) based on risk for developing RCC. The genotype/phenotype correlations within each type are described in Table 40.2.

Renal Lesions

RCCs of patients with VHL disease are of exclusively clear cell histology. The lifetime risk for developing RCC is 25% to 45%, and when renal cysts are included, the risk rises to 60%.⁵ Renal cysts and RCCs develop at an earlier age in patients with VHL in comparison to sporadic counterparts, with an average age of 39 years (range, 16 to 67 years).⁵ Cystic lesions are typically asymptomatic; however, complex cysts must be monitored closely with computed tomography (CT) or magnetic resonance imaging as they will harbor a visibly solid RCC component. RCC will often arise from noncystic parenchyma as well.

Nonrenal Clinical Features

With the exception of RCC and pancreatic NETs, the malignancy risk with VHL-associated tumors is very low. Renal lesions and hemangioblastoma of the cerebellum, spine, or retina are common presenting lesions in VHL. The risk for developing a single hemangioblastoma of the spine, cerebellum, and brainstem is 60% to 80%, and the average age is 33 years (range, 9 to 73 years),⁵ although most patients can develop multiple lesions at any point in their lifetime. Patients may remain completely asymptomatic, especially during periods of no growth or slow growth. Surgical resection is delayed until onset of symptoms.

Retinal hemangioblastomas (retinal angiomas) are usually multifocal and bilateral. These hypervascular tumors can lead to retinal detachment and vision loss. Retinal hemangioblastomas have been observed in 25% to 60% of patients with an average age of 25 years (range, 1 to 67 years). Approximately 5% of lesions are seen younger than 10 years, making genetic testing of at-risk children essential as affected children should undergo annual retinal examinations beginning at birth. Pheochromocytoma has also been observed in young children and can present as a hypertensive crisis. The average age at presentation is 30 years (range, 5 to 58 years), and the risk is 10% to 20%.⁵

Pancreatic manifestations include multiple simple cysts and serous cystadenomas (47% and 11%, respectively), which follow a benign course and are almost always asymptomatic in patients. Pancreatic NETs are less common (15%); however, approximately 2% undergo malignant transformation.⁶ A NET tends to be indolent and is seldom the initial presenting lesion; however, close monitoring is indicated for timing of surgical resection. A less common manifestation of VHL is a papillary cystadenoma of the endolymphatic sac, or inner ear, which is extremely rare in the general population but more prevalent in VHL disease (˜11%). Papillary cystadenomas may also arise in the epididymis in men and less commonly in the adnexal organs in women.

TABLE 40.1 Genetic Susceptibility to Renal Cell Carcinoma

Syndrome	Acronym	Gene(s)	Phenotype	RCC Type	Genetic Testing Sensitivity
von Hippel-Lindau syndrome	VHL	VHL	Hemangioblastoma (cerebellum, spine, retina), pheochromocytoma, papillary cystadenoma (pancreas, epididymis, adnexal organs, endolymphatic sac pancreatic NET, and cysts)	Clear cell	Nearly 100%^a
Birt-Hogg-Dubé syndrome	BHD	Folliculin, FLCN	Fibrofolliculoma, trichodiscoma, acrochordon, lung cysts, spontaneous pneumothorax	50% chromophobe/oncocytic hybrid, 34% chromophobe, 9% clear cell, 5% oncocytoma, 2% papillary	˜88%²⁰
Hereditary leiomyomatosis and RCC	HLRCC	FH	Cutaneous leiomyoma, uterine leiomyoma	Papillary type 2	˜93%²⁵
Hereditary papillary RCC	HPRCC	MET	No additional features	Papillary type 1	Not well established as families are rare
Hereditary paraganglioma/pheochromocytoma	HPGL	SDHB, possibly SDHD and SDHC	Pheochromocytoma and paraganglioma	Not well defined, but clear cell and papillary types reported	Unknown in families with RCC and no paraganglioma or pheochromocytoma
RCC, renal cell carcinoma; NET, neuroendocrine tumor.
^aStolle C, Glenn G, Zbar B, et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12:417-423.

von Hippel-Lindau Molecular Genetics

The VHL gene was cloned by Latif et al.⁷ in 1993 and is the most well studied of the familial RCC syndromes. Loss of VHL function has been demonstrated to cause RCC formation in VHL disease as well as in the majority of sporadic clear cell RCCs.⁸^,⁹ The VHL gene encodes the pVHL protein, which in normoxic conditions forms a complex with elongin B, elongin C, Cullin 2, and Rbx1. The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. The HIF-1α and HIF-2α genes, along with HIF-3α, encode the α subunit of the HIF heterodimer. In hypoxic conditions, the VHL complex does not interact with HIF-1α and HIF-2α, leading to an accumulation of these subunits and downstream transcription of HIF-dependent genes. Loss of VHL protein function in renal tumors simulates low tissue oxygen levels, or “pseudohypoxia,” where HIF-1α and HIF-2α accumulate, causing upregulation of many genes involved in tumorigenesis such as vascular endothelial growth factor (proangiogenesis), epidermal growth factor receptor (cell proliferation and survival), and glucose transporter 1 (regulation of glucose uptake).

TABLE 40.2 von Hippel-Lindau Genotype Phenotype Correlations

VHL Phenotype	Pheo	RCC	HB	Predominant Mutation Type
Type 1	Rare or absent	High	High	Large deletions, nonsense, frameshift
Type 2A	High	Rare	High	Missense
Type 2B	High	High	High	Missense
Type 2C (uncommon)	High	Absent	Absent	Missense
Note: The majority of type 1 mutations are partial or complete deletions and protein truncating (nonsense and frameshift), whereas 96% of type 2 mutations are missense. Missense mutations that disrupt amino acid residues on the surface of the VHL protein confer a higher Pheo risk than missense mutations that disrupt protein structure.
VHL, von Hippel-Lindau; Pheo, pheochromocytoma; RCC, renal cell carcinoma; HB, hemangioblastoma.
From Maher ER, Webster AR, Richards FM, et al. Phenotypic expression in von Hippel-Lindau disease: Correlations with germline VHL gene mutations. J Med Genet 1996;33:328-332; and Ong KR, Woodward ER, Killick P, et al. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat 2007;28:143-149.

von Hippel-Lindau Genetic Testing

Genetic testing of the VHL gene is available on a clinical basis and involves full-gene sequencing and large gene rearrangement analysis. When both methods are used, the mutation detection rate is nearly 100% in patients with a clinical diagnosis of VHL.¹⁰ Approximately 80% of patients have a parent with VHL, and ˜20% represent de
novo cases where neither parent carries the mutation. Genetic testing is recommended for a proband with a personal and family history of VHL, as the identification of causative mutations aids in determining disease subtype (see Table 40.2). Disease subtype information along with a careful, detailed family history aids in guiding screening and surveillance of patients with VHL. In simplex cases, where a patient has two or more VHL-associated lesions and a negative family history, genetic testing is recommended to establish a diagnosis. When a mutation is identified in a proband, at-risk family members should be offered predictive testing. Since young children with VHL are known to be at risk for retinal lesions and pheochromocytoma, genetic testing should be offered any time after birth.

Birt-Hogg-Dubé Syndrome

In 1977, Drs. Birt, Hogg, and Dubé first described a multigenerational kindred showing autosomal dominant transmission of fibrofolliculomas with trichodiscomas and acrochordons.¹¹ The phenotype was later expanded beyond dermatologic manifestations to include lung cysts and pneumothorax and renal tumors.¹² The number of families with BHD syndrome described in the literature to date is small, and therefore, the exact incidence is unknown. Inherited mutations in the folliculin (FLCN) gene are associated with BHD syndrome.

Renal Lesions

An individual with BHD syndrome is at increased risk of developing multiple and bilateral renal tumors, frequently of more than one histologic type even within the same renal unit, and at younger ages compared with the general population. The lifetime risk is in the range of 27% to 45%,¹³^,¹⁴ and the wide range may be a reflection of ascertainment bias introduced when families are recruited predominantly through dermatology clinics versus urology. The most common tumor pathology found in patients is a hybrid oncocytic RCC, which contains a mixture of oncocytic and chromophobe cells. Furthermore, radical nephrectomy specimens of patients have demonstrated oncocytosis where tiny nodules of cells similar to the larger hybrid tumors are diffusely scattered throughout the renal parenchyma. A retrospective study by Pavlovich et al.¹⁵ examined 130 tumor specimens from 30 patients (25 males, 5 females) in 19 different BHD families. The authors found that hybrid oncocytic (50%) and chromophobe (34%) were the more common histologic findings, followed by clear cell (9%), benign oncocytoma (5%), and papillary (2%). The average age at first tumor was 50.7 years, and patients averaged 5.3 tumors each (range, 1 to 28). Other studies reporting histologic subtypes of BHD syndrome-related renal tumors have similar findings.

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