RenalNext

RenalNextTM is a next generation sequencing panel that simultaneously analyzes 19 genes associated with increased risk for kidney cancer.

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RenalNextTM is a next generation sequencing panel that simultaneously analyzes 19 genes associated with increased risk for kidney cancer.

Ambry utilizes next generation sequencing (NGS) to offer a comprehensive hereditary kidney cancer panel.  Genes on this panel include: BAP1, EPCAM, FH, FLCN, MET, MITF, MLH1, MSH2, MSH6, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, TP53, TSC1, TSC2, VHL. Full gene sequencing is performed for 18 of the genes (excluding EPCAM). For MITF, only the status of the c.952G>A (p.E318K) alteration is analyzed and reported. Gross deletion/duplication analysis is performed for 18 genes (excluding MITF). Specific Site Analysis is available for individual gene mutations identified in a family.

Disease Name 
Hereditary cancer
Kidney cancer
Renal cell carcinoma
Disease Information 

Kidney cancer affects about 1 in 60 (1.6%) of men and women in the U.S. in their lifetime and is the seventh and eighth most common cancer in men and women, respectively.1 Renal cell carcinoma (RCC) is a complex disease with a diverse spectrum of tumor subtypes, including clear cell or conventional (70-80%), papillary type 1 and type 2 (10-15%), chromophobe (3-5%), and collecting duct (1%).2  Approximately 3-5% of RCC cases are hereditary3-5 and occur as a result of an inherited mutation in one or more genes. Unlike sporadic RCC cases, hereditary RCC is often characterized by earlier disease onset and/or multifocal or bilateral tumors.2


RenalNext Panel Genes:

BAP1 mutations have been shown to cause a tumor predisposition syndrome characterized by uveal melanoma, cutaneous melanoma, renal cell carcinoma, asbestos exposure-induced mesothelioma, and nonmalignant melanocytic BAP1-mutated atypical intradermal tumors (MBAITs).6-9  Lifetime cancer risks are increased, but are not well defined. 

FH  is a gene associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is characterized by an increased lifetime risk of developing papillary type 2 renal tumors, with a lifetime risk of up to 20% for renal cancer and nearly 98% risk of cutaneous and uterine leiomyomas/fibroids.10 HLRCC-associated renal tumors are more likely to present as unilateral solitary lesions, with about 20% of individuals identified in their forties at an age range of 17-75 years. Almost all female HLRCC mutation carriers have uterine fibroids, with a mean age of diagnosis at 30 years, and an age range of 18-52 years.4,5,10,11  Although uterine fibroids are common in the general population, the fibroids in women with HLRCC tend to be larger and more numerous.

FLCN gene mutations cause Birt-Hogg-Dubé (BHD), an autosomal dominant hereditary renal cancer syndrome. A classic triad of findings characterizes BHD, which includes cutaneous fibrofolliculomas (benign skin tumors), pulmonary cysts, and renal tumors.4,12  Pulmonary cysts are found in approximately 80% of affected individuals, while bilateral renal tumors affect up to 34% of individuals. Secondary clinical findings can include spontaneous pneumothoraces, colorectal adenomas, parathyroid adenomas, neural tissue tumors, lipomas, angiolipomas, and connective tissue abnormalities. Individuals with BHD have about a 34% lifetime risk for renal cancer, most frequently diagnosed in the fifties.12-14  Additionally, male FLCN mutation carriers are twice as likely to be affected as female carriers.15,16  Approximately 50% of BHD-related renal tumors manifest as a chromophobe/oncocytic hybrid: 34% chromophobe, 9% clear cell, 5% oncocytoma, and 2% papillary.17

MET  is a proto-oncogene associated with hereditary papillary renal carcinoma (HPRC). HPRC is an autosomal dominant disorder with high penetrance, characterized by increased risk for bilateral (or multifocal type 1) papillary renal cancer. HPRC-associated renal cancer has a median age of onset of 60-80 years.4,5,11  Furthermore, HPRC renal tumors show frequent somatic trisomy of chromosome 7, and earlier-onset carcinoma can be attributed to germline missense mutations in the tyrosine kinase domain of the MET proto-oncogene.18

MITF is a gene implicated in both melanoma and renal cell carcinoma (RCC) development pathways.19,20  As such, MITF mutation carriers have an increased predisposition to developing melanoma and/or RCC. A specific mutation with unique functional consequences, p.E318K, has been detected at increased frequency in both melanoma and RCC cohorts.19,20  Carriers of the p.E318K mutation have over a five-fold increased risk of developing RCC, melanoma, or both.19

MLH1, MSH2, MSH6, PMS2, and EPCAM germline mutations are associated with Lynch syndrome (previously called hereditary non-polyposis colorectal cancer, HNPCC). Lynch syndrome is an autosomal dominant condition estimated to cause 2-5% of all colorectal cancer. It is associated with a significantly increased risk for colorectal cancer (up to 82% lifetime risk), uterine/endometrial cancer (25-60% lifetime risk in women), stomach cancer (6-13% lifetime risk), and ovarian cancer (4-12% lifetime risk in women). Risk for cancer of the small bowel, hepatobiliary tract, upper urinary tract (including transitional cell carcinoma of the renal pelvis), brain, and sebaceous glands may also be elevated.21-25

PTEN is a gene associated with Cowden syndrome (CS), PTEN hamartoma tumor syndrome (PHTS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and autism spectrum disorder. CS is a multiple hamartoma syndrome with a high risk of developing tumors of the thyroid, breast, and endometrium. Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease, multiple uterine leiomyomata, and macrocephaly can also be seen. Affected individuals have a lifetime risk of up to 50% for breast cancer, 10% for thyroid cancer, and 5-10% for endometrial cancer. Over 90% of individuals with CS will express some clinical manifestations by their twenties.26,27  Recent studies noted increased risks for renal cell cancer, colorectal cancer, and other cancers.28,29  One study quotes up to a 31-fold increase in RCC risk for PTEN mutation carriers as compared to the general population.30

SDHA, SDHB, SDHC, and SDHD are all genes associated with hereditary paraganglioma and pheochromocytoma (PGL/PCC) syndrome. Germline mutations in these genes have been associated with susceptibility to head and neck paragangliomas (HNPGLs), extra-adrenal PGLs/PCCs and, rarely, RCC with gastrointestinal stromal tumors (Carney-Stratakis syndrome).31  SDHB associated RCC can be of varied histology with reported cases of clear cell, papillary, granular, and mixed.32,33  The exact lifetime risk for PCC is not yet established for SDHB mutation carriers.34  The SDHD gene is subject to the effects of imprinting (parent-of-origin effects), and cancer risk is correlated with paternal transmission.35  Mutations in the SDH genes have also been associated with PTEN mutation-negative Cowden syndrome.36

TP53 is a tumor suppressor gene, and germline mutations within it are associated with Li-Fraumeni syndrome (LFS). An individual carrying a TP53 mutation has a 21-49% lifetime risk of developing cancer by age 30 and a lifetime cancer risk of 68-93%.37  The most common tumor types observed in LFS families include soft tissue and osteosarcomas, breast cancer, brain tumors (including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas), and adrenocortical carcinoma (ACC); other cancers, including colorectal, gastric, ovarian, pancreatic, and renal, have also been reported.38,39  Studies have shown that a small percentage of women with early-onset breast cancer that do not carry BRCA1 and BRCA2 mutations are identified to have mutations in TP53.40-42

TSC1 and TSC2 are genes associated with tuberous sclerosis complex (TSC), a multi-system neurocutaneous disorder characterized by presence of benign hamartomas in multiple tissues and organs, seizures, and intellectual disability.43  Benign hamartomas can be found in the heart (rhabdomyomas), brain (astrocytomas), kidneys (angiomyolipomas), skin, eyes, lungs (pulmonary lymphangioleimyomatosis), skeleton, and endocrine glands.43-47  The lifetime risk of renal cancer development in TSC is 2-5%.44

VHL mutations are associated with von Hippel-Lindau disease (VHL). VHL is an autosomal dominant cancer predisposition syndrome with about a 20% de novo mutation(48) rate and an estimated incidence of 1 in 36,000.11 VHL is characterized by renal tumors, adrenal pheochromocytoma (PCC), retinal angiomas, central nervous system hemangioblastomas, pancreatic cysts, and neuroendocrine tumors. The associated lifetime risk of RCC in those with VHL is estimated at 25-70%, depending on disease subtype. VHL-associated renal tumors tend to be earlier-onset (average age of diagnoses is 39 years) and multifocal.48  Published literature supports that patients carrying a partial germline VHL gene deletion have a higher RCC risk than those carrying full-gene deletions.5,11

Testing Benefits & Indication 


Indications for Testing
RenalNext may be appropriate in the following situations, combined with common red flags for hereditary cancer:

  • Early-onset kidney cancer (diagnosed 45 years of age)
  • Multiple primary cancers in one person (e.g. two primary kidney cancers, or kidney and thyroid cancer)
  • ≥2 family members with kidney cancer*
  • ≥3 family members with kidney and other cancers*
  • Multiple close family members with kidney and neuroendocrine tumors*
    *On the same side of the family


Common Red Flags for Hereditary Cancer

  • Cancer diagnosed at a younger age than expected for the general population (≤ 50 years, for most cancers)
  • Cancer diagnosed across generations, and in multiple generations within a family, especially when diagnosed younger than average
  • Individual with multiple primary cancers (either in paired organs or in different organs)
  • A pattern of cancer in the family that is typical of a known cancer predisposition syndrome (pulmonary cysts and kidney tumors with FLCN)

Benefits of Testing
Identifying patients with an inherited susceptibility for certain cancers can help with medical management. For example, this information can:

  • Modify cancer surveillance options and age of initial screening
  • Suggest specific risk-reduction measures (e.g. considering prophylactic oophorectomy, after childbearing is complete, for women with increased risk for uterine and/or ovarian cancer)
  • Clarify and stratify familial cancer risks, based on gene-specific cancer associations, such as risk for uterine, colon, and ovarian cancer with MLH1 mutations
  • Offer treatment guidance (e.g. avoidance of radiation-based treatment methods for individuals with a TP53 mutation)
  • Identify other at-risk family members
  • Provide guidance with new gene-specific treatment options and risk reduction measures as they emerge
Test Description 

RenalNext analyzes 19 genes (BAP1, EPCAM, FH, FLCN, MET, MITF, MLH1, MSH2, MSH6, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, TP53, TSC1, TSC2, VHL). 18 genes (excluding EPCAM) are evaluated by NGS or Sanger sequencing of all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. In addition, sequencing of the promoter region is performed for the following genes: PTEN (c.-1300 to c.-745), MLH1 (c.-337 to c.-194), and MSH2 (c.-318 to c.-65). For MITF, only the status of the c.952G>A (p.E318K) alteration is analyzed and reported. The inversion of coding exons 1-7 of the MSH2 gene is detected by NGS and confirmed by PCR and agarose gel electrophoresis. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing. Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of 18 genes (excluding MITF) using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. If a deletion is detected in exons 13, 14, or 15 of PMS2, double stranded sequencing of the appropriate exon(s) of the pseudogene, PMS2CL, will be performed to determine if the deletion is located in the PMS2 gene or pseudogene.   

Mutation Detection Rate 

RenalNext can detect >99.9% of described mutations in the included genes listed above, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME (days)
5900 RenalNext 14 - 21

 

Specialty 
Genes 
MLH1
MSH2
MSH6
PMS2
PTEN
TP53
VHL
EPCAM
FLCN
TSC2
TSC1
SDHB
MET
MITF
SDHC
SDHD
SDHA
FH
BAP1
References 
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  4. Coleman JA, Russo P. Hereditary and familial kidney cancer. Current Opinion in Urology. 2009;19(5):478-85. 
  5. Rini BI, Campbell SC, Rathmell WK. Renal cell carcinoma. Current Opinion in Oncology. 2006;18(3):289-96. 
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  7. Popova T, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 2013;92:974-80.
  8. Testa JR, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022-5.
  9. Wiesner T, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43(10):1018-21.
  10. Gardie B, et al. Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet. 2011;48(4):226-34. 
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