Genetic predisposition to kidney cancer

Abstract

Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube´syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase-associated renal cancer were identified. Recently, renal cell carcinoma has been confirmed as part of the clinical phenotype in individuals from families with BAP1-associated tumor predisposition syndrome and MiTF-associated cancer syndrome. Here we summarize the clinical characteristics of and causative genes for these and other inherited RCC syndromes, the pathways that are dysregulated when the inherited genes are mutated, and recommended clinical management of patients with these inherited renal cancer syndromes.

Keywords: Birt-Hogg-Dubé syndrome; Hereditary leiomyomatosis and renal cell carcinoma; Hereditary papillary renal carcinoma; Inherited renal cancer syndromes; Kidney neoplasms; Von Hippel-Lindau.

Fig. 1

Hereditary kidney cancer. Kidney cancer is not a single entity but made up of a number of different types of cancer, each with a distinct histology, caused by a different gene, with a different clinical course, and responding differently to therapy. Germline von Hippel-Lindau (VHL) gene mutations cause von Hippel-Lindau disease and clear cell kidney tumors. Germline MET oncogene mutations predispose to hereditary papillary renal carcinoma with type 1 papillary tumors. Germline mutations in the folliculin (FLCN) gene are inherited in patients with Birt-Hogg-Dubé syndrome who present with hybrid oncocytic tumors, chromophobe renal tumors and benign oncocytomas. Germline fumarate hydratase (FH) gene mutations in patients with hereditary leiomyomatosis and renal cell carcinoma predispose affected individuals to develop renal tumors with papillary type 2 histology. Germline mutations in the genes encoding subunits of succinate dehydrogenase, SDHB/SDHC/SDHD, predispose to renal tumors with an oncocytic phenotype in SDH-deficient RCC patients. Patients with tuberous sclerosis complex inherit germline mutations in tuberous sclerosis complex 1 or 2 (TSC1, TSC2) genes and are at risk to develop angiomyolipomas in the kidney and, occasionally, renal tumors. Adapted and reprinted with permission [97].

Fig. 2

Clinical manifestations of von Hippel-Lindau disease. (A) Contrast-enhanced MRI of a cerebellar hemangioblastoma (arrow) with an associated cyst (adjacent dark area) in a 40-year-old VHL patient. (B) Bilateral multifocal renal tumors (arrows) and multiple cysts in a 22-year-old VHL patient. (C) Bilateral pheochromocytomas (arrows) in the adrenal glands of a 29-year-old VHL patient. (D) Pancreatic neuroendocrine tumor (arrow) in the pancreas of a VHL patient. Adapted and reprinted with permission [98].

Fig. 3

Clinical manifestations of Birt-Hogg-Dubé syndrome. (A) Multiple fibrofolliculomas on the forehead of a BHD patient (arrows). (B) Chest CT scan of a BHD patient showing bilateral multiple pulmonary cysts (arrows) that can lead to spontaneous pneumothorax. (C,D) Abdominal CT scans demonstrating bilateral multifocal renal tumors in BHD patients (arrows). Adapted and reprinted with permission [54].

Fig. 4

Clinical manifestations of hereditary leiomyomatosis and renal cell carcinoma. (A) Multiple cutaneous leiomyomas in an HLRCC patient. (B) CT image showing multiple large uterine leiomyomas (arrows) that occur in HLRCC. (C) Para-aortic nodal disease (arrow) and (D) renal tumor (arrow) in patients with HLRCC. Adapted and reprinted with permission [60].