Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test

Nguyen, Kevin A.; Syed, Jamil; Espenschied, Carin R.; LaDuca, Holly; Bhagat, Ansh; Suarez‐Sarmiento, Alfredo; O’Rourke, Timothy K.; Brierley, Karina L.; Hofstatter, Erin; Shuch, Brian

doi:10.1002/cncr.30893

Cited by 43 publications

(35 citation statements)

References 27 publications

(55 reference statements)

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“…While factors including smoking, environment, obesity, and race have been linked to increased risk of RC, inherited factors are the most well-validated source of increased risk 2 – 4 . Hereditary RC syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance ‘RC-specific’ genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 5 – 7 . A previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene 7 .…”

Section: Introductionmentioning

confidence: 99%

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Hartman

Demidova

Lesh

et al. 2020

Sci Rep

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Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC. Renal cancer (RC) often develops with no signs or symptoms and is referred to as the "silent disease" 1. While factors including smoking, environment, obesity, and race have been linked to increased risk of RC, inherited factors are the most well-validated source of increased risk 2-4. Hereditary RC syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance 'RC-specific' genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 5-7. A previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene 7. However, for most eoRC patients a PV in an RC-specific gene is not identified, leaving many eoRC genetically undefined. Thus, there is a need to identify additional genes related to eoRC risk. Currently, there are no National Comprehensive Cancer Network (NCCN) guidelines for detection, prevention, or risk reduction in individuals who present with an eoRC but lack a PV in a defined RC-specific gene 8 .

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Section: Introductionmentioning

confidence: 99%

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Hartman

Demidova

Lesh

et al. 2020

Sci Rep

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“…Hereditary RC (hRC) syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance 'RC-specific' genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 (2-4). Previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene (4).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Hartman

Demidova

Lesh

et al. 2020

Preprint

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Purpose: Pathogenic variants (PVs) in a number of genes are known to increase the risk of hereditary renal cancer (hRC). However, many early-onset RC (eoRC) patients undergoing genetic testing lack PVs in hRC genes; thus, their genetic risk remains undefined. To determine if PVs in DNA damage response (DDR) genes are enriched in a convenience sample of eoRC patients undergoing genetic testing. Materials and Methods: Retrospective review of results for 844 unselected eoRC patients, undergoing genetic testing with a multi-gene cancer panel by Ambry Genetics [between July 2012 and December 2016]. The patients were tested with CancerNext and/or CancerNext Expanded panels for a variety of indications. Identified PVs were compared with patient characteristics.Results: Mean age of RC diagnosis was 48 years [range 24-60]. In addition to eoRC, 57.9% patients tested reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). PVs in cancer risk genes were identified in 12.8% of patients-3.7% in RC-specific genes, and 8.55% in DDR genes. DDR gene PVs were most commonly identified in CHEK2, BRCA1/2, and ATM. Among the 2.1% of patients with a BRCA1/2 PV, <50% reported a personal history of hereditary breast/ovarian-associated cancer.No association between age of RC diagnosis, and prevalence of PVs in RC-specific or DDR genes was observed. Conclusions:Multi-gene panel testing including DDR genes may provide a more comprehensive risk assessment in unselected eoRC patients, and their families. Validation in larger datasets is needed to characterize the association with eoRC.

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“…(2) those with multifocal or bilateral renal masses, and (3) individuals for whom a personal or family history suggests a familial renal neoplastic syndrome. However, using strict referral criteria such as a family history of kidney cancer will miss more than two-thirds of cases among individuals diagnosed with a hereditary cancer syndrome [4,5]. Incomplete family histories, diverse presentations, incomplete penetrance, and de novo germline mutations all contribute to difficulty in relying on family history alone [6].…”

Section: Introductionmentioning

confidence: 99%

“…The type of testing has also evolved and single-gene testing does not need to be performed unless there is a clear clinical diagnosis or when family cascade testing is pursued. Many companies have specific renal panels that include 15-20 relevant genes associated with kidney cancer [5]. However, a family pedigree may also highlight other concerns, and testing that is too narrow can miss important considerations for hereditary cancer risk (Fig.…”

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confidence: 99%

Genetic Testing in Kidney Cancer Patients: Who, When, and How?

Lui

Shuch

2019

European Urology Focus

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Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test

Cited by 43 publications

References 27 publications

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

Genetic Testing in Kidney Cancer Patients: Who, When, and How?

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