Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) 2/6 –Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version

Major Heritable Renal Cell Cancer Syndromes

Four major heritable renal cell cancer (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal carcinoma [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.

Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes

ENLARGE

Syndrome (Inheritance Pattern)	Gene Locus, Gene Type (Protein)	Renal Tumor Pathology	Cumulative Cancer Risk	Nonrenal Tumors and Associated Abnormalities
AD = autosomal dominant; ccRCC = clear cell renal cell cancer; CNS = central nervous system.
von Hippel-Lindau disease (VHL) (AD) [1,2]	VHL 3p26, tumor suppressor (pVHL)	ccRCC (multifocal)	24%–45%	CNS hemangioblastoma, retinal hemangioblastomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of the pancreas, the epididymis, and the broad ligament
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD) [3-6]	FH 1q42.1, tumor suppressor (fumarate hydratase)	‘HLRCC-type RCC’ may be new entity (formerly called papillary type 2)	Up to 32%	Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Birt-Hogg-Dubé syndrome (BHD) (AD) [7-10]	FLCN 17p11.2, tumor suppressor (folliculin)	Chromophobe oncocytic hybrid, papillary clear cell oncocytoma	15%–30%	Cutaneous: fibrofolliculomas/ trichodiscomas
				Pulmonary: lung cysts, spontaneous pneumothoraces
Hereditary papillary renal carcinoma (HPRC) (AD) [11,12]	MET 7q34, proto-oncogene (hepatocyte growth factor receptor)	Papillary type 1	Approaching 100%	None known

Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Autosomal dominant means that it is sufficient for the altered gene to be present in one of the parents and that the chances of transmitting this gene and the disease to the offspring is 50% for each pregnancy. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for the genes associated with VHL, BHD, HLRCC, and HPRC. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

References

1. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995. [PUBMED Abstract]
2. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
3. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PUBMED Abstract]
4. Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005. [PUBMED Abstract]
5. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PUBMED Abstract]
6. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PUBMED Abstract]
7. Toro JR, Wei MH, Glenn GM, et al.: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 45 (6): 321-31, 2008. [PUBMED Abstract]
8. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PUBMED Abstract]
9. Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11 (4): 393-400, 2002. [PUBMED Abstract]
10. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002. [PUBMED Abstract]
11. Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
12. Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]