Renal Cancer Panel

Renal cell carcinoma is the most common type of kidney cancer and includes many subtypes such as clear cell, papillary, chromophobe, and oncocytoma; these account for approximately 75%, 12%, 5%, and 4% of cases, respectively. Although most of these renal tumors occur sporadically, about 3% of renal cell carcinomas (RCC) are considered familial (Maher. 2011. PubMed ID: 21071978). Other less common types of kidney cancer that can also be familial include transitional cell carcinomas, Wilms tumor, and renal sarcomas (http://www.cancer.org/). Hereditary renal cancers are often multifocal or bilateral. Individuals with hereditary renal cancers are often diagnosed at earlier ages, and they may also have other physical characteristics associated with specific syndromes (Coleman and Russo. 2009. PubMed ID: 19584731; Linehan et al. 2010. PubMed ID: 20448661). Diseases that have renal cancer as a clinical feature include Birt-Hogg-Dube syndrome, CDC73-related disorders, DICER1 syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), hereditary papillary renal cell carcinoma (HPRCC), hereditary paraganglioma-pheochromocytoma syndrome, Li-Fraumeni syndrome, Lynch syndrome, Perlman syndrome, PTEN hamartoma tumor syndrome, rhabdoid tumor predisposition syndrome, tuberous sclerosis, tumor predisposition syndrome, Von Hippel-Lindau disease, and Wilms tumor.

The renal cancer next generation sequencing panel assesses genes that have been shown to be involved in disorders that have renal cancer as a clinical feature. They are inherited in an autosomal dominant manner with the exception of DIS3L2, which is autosomal recessive.

BAP1 is a tumor suppressor gene that encodes a deubiquitinating enzyme containing numerous functional domains, including the ubiquitin C-terminal hydrolase (UCH) domain, a host cell factor-1 (HCF-1) binding domain and binding domains for BRCA1 and BARD1. BAP1 has been functionally implicated in numerous biologic processes, including chromatin dynamics, DNA damage response, and regulation of the cell cycle and cell growth (Goldstein. 2011. PubMed ID: 21956388). BAP1 pathogenic variants have been associated with clear cell renal cancer (Nguyen et al. 2017. PubMed ID: 28787086; Maher. 2018. PubMed ID: 29680948).

CDC73 encodes parafibromin, which is a tumor suppressor that is involved in regulating the cell cycle and gene expression (Bradley et al. 2006. PubMed ID: 16487440; Masi et al. 2008. PubMed ID: 18755853). CDC73 pathogenic variants are associated with papillary RCC and Wilms tumor (Maher. 2018. PubMed ID: 29680948).

CHEK2 encodes a protein kinase. Pathogenic variants in this gene are associated with breast cancer, but have also been reported in individuals with advanced renal cancer (Carlo et al. 2018. PubMed ID: 29978187).

DICER1 syndrome is caused by pathogenic variants in DICER1, which encodes an RNase endonuclease that is involved in the production of microRNAs (miRNAs). Deregulation of miRNA processing and expression has been implicated in numerous cancers. DICER1 pathogenic variants are hypothesized to result in haploinsufficiency (Slade et al. 2011. PubMed ID: 21266384); however, DICER1 mutations may exhibit incomplete penetrance as some individuals with DICER1 mutations appear phenotypically normal (Hill et al. 2009. PubMed ID: 19556464). DICER1 pathogenic variants have been associated with renal sarcoma and Wilms tumor (Schultz et al. 2018. PubMed ID: 29343557).

Perlman syndrome is inherited in an autosomal recessive manner, and is caused by pathogenic variants in the DIS3L2 gene. This gene encodes an exonuclease and is thought to have a role in cellular RNA metabolism (Lubas et al. 2013. PubMed ID: 23756462). Pathogenic variants are found in the RNA-binding (RNB) domain, which may lead to disrupted exonuclease activity (Astuti et al. 2012. PubMed ID: 22306653; Morris et al. 2013. PubMed ID: 23613427). DIS3L2 inactivation by pathogenic variants is also associated with mitotic abnormalities, and knockdown of this gene enhances cellular growth (Astuti et al. 2012. PubMed ID: 22306653). Individuals with Perlman syndrome are at a high risk of Wilms tumor (Morris et al. 2013. PubMed ID: 23613427).

FH pathogenic variants are responsible for HLRCC and are associated with type 2 papillary renal tumors. It is thought that FH pathogenic variants result in a loss of function leading to increases in cellular fumurate. This increase causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes further downstream in the HIF pathway leading to tumor formation (Pithukpakorn et al. 2015. PubMed ID: 20301430; Badeloe and Frank. 2009. PubMed ID: 19939761).

FLCN pathogenic variants cause Birt-Hogg-Dube syndrome. The FLCN gene is a putative tumor suppressor that acts downstream of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) and may have a role in the modulation of energy/nutrient sensing and signaling pathways (Hartman et al. 2009. PubMed ID: 19234517). Pathogenic variants in FLCN have been associated with chromophobe/oncocytic renal cell carcinoma (Maher. 2018. PubMed ID: 29680948).

MET pathogenic variants cause HPRCC, which is associated with type 1 papillary renal tumors. Pathogenic variants in the MET oncogene lead to ligand-independent activation of the tyrosine kinase domain of the protein, which results in constitutive activation of the hepatocyte growth factor (HGF)/c- Met pathway (Coleman and Russo. 2009. PubMed ID: 19584731).

MITF, which encodes the microphthalmia-associated transcription factor, helps control the development and function of pigment-producing cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. Pathogenic variants in MITF alter protein dimerization impacting melanocyte development (Widlund and Fisher. 2003. PubMed ID: 12789278). A pathogenic variant in MITF has been associated with renal cancer (Schmidt and Linehan. 2016. PubMed ID: 27899189; Nguyen et al. 2017. PubMed ID: 28787086).

Pathogenic variants in the EPCAM, MLH1, MSH2, MSH6, and PMS2 genes cause Lynch syndrome and are associated with transitional cell carcinomas of the renal pelvis and ureter (Nguyen et al. 2017. PubMed ID: 28787086; Carlo et al. 2018. PubMed ID: 29978187). Most of these genes are involved in mismatch repair. Pathogenic variants result in defective DNA repair leading to cancer. The exception is EPCAM, which encodes a calcium-independent cell adhesion molecule.

PTEN and TP53 pathogenic variants cause PTEN hamartoma syndrome and Li-Fraumeni syndrome, respectively. These genes encode for tumor suppressors, and pathogenic variants have been associated with renal cell carcinoma (Carlo et al. 2018. PubMed ID: 29978187; Maher. 2018. PubMed ID: 29680948).

Pathogenic variants in the SDHA, SDHB, SBHC, SDHD genes cause hereditary paraganglioma and pheochromocytoma syndrome. The tested SDH genes are nuclear genes, which encode subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). Pathogenic variants in these genes have been associated with renal cancer (Maher. 2018. PubMed ID: 29680948; Carlo et al. 2018. PubMed ID: 29978187).

SMARCB1 pathogenic variants cause rhabdoid tumor predisposition syndrome and predisposes individuals to renal and extrarenal malignant rhabdoid tumors. SMARCB1 encodes a tumor suppressor that functions as a member of the human ATP-dependent SWI/SNF complex, which has a role in epigenetic modification by regulating gene transcription and DNA repair (Reisman et al. 2009. PubMed ID: 19234488).

Pathogenic variants in the TSC1 and TSC2 genes cause tuberous sclerosis, which is associated with renal cell carcinoma and angiomyolipoma. These genes encode tumor suppressors that are involved in cellular proliferation and act through multiple signaling pathways (e.g. mTOR/AKT pathways) (Orlova and Crino. 2010. PubMed ID: 20146692).

VHL pathogenic variants cause Von Hippel-Lindau disease. A major clinical feature of this disease is renal clear cell carcinoma. The VHL gene is a tumor suppressor, and its protein product requires inactivation of both alleles at the cellular level leading to abnormal activation of genes involved in hypoxia (Maher et al. 2011. PubMed ID: 21386872).

Pathogenic variants in the WT1 gene cause Wilms tumor. WT1 encodes a tumor suppressor that interacts with the Wnt/beta-catenin signaling pathway and many other downstream targets of cellular growth, differentiation and apoptosis (Md Zin et al. 2011. PubMed ID: 21516053).

See the individual gene test descriptions for additional information.

In a study of 254 patients with advanced renal cell carcinoma, germline pathogenic variants from 76 cancer predisposition genes were found in 16.1% of patients (Carlo et al. 2018. PubMed ID: 29978187). Renal cell carcinoma-associated pathogenic variants were found in the BAP1, FH, MET, SDHA, SDHB, and VHL genes, but other cancer-associated pathogenic variants were observed in CHEK2, EPCAM, MSH6 and other genes.

Another study that analyzed 19 genes in 1235 patients with kidney cancer observed that 6.1%, 75.5%, and 18.4% of individuals had positive, negative, and inconclusive results, respectively (Nguyen et al. 2017. PubMed ID: 28787086). The most common pathogenic variants were found in FLCN, FH, MITF, SDHB, and PMS2, but variants in other genes were also detected.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired.