TY - JOUR

T1 - Exploring the hereditary background of renal cancer in Denmark

AU - Christensen, Maria Bejerholm

AU - Wadt, Karin

AU - Jensen, Uffe Birk

AU - Lautrup, Charlotte Kvist

AU - Bojesen, Anders

AU - Krogh, Lotte Nylandsted

AU - Overeem Hansen, Thomas van

AU - Gerdes, Anne-Marie

PY - 2019

Y1 - 2019

N2 - BACKGROUND: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition.METHODS: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue.RESULTS: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B.CONCLUSION: Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.

AB - BACKGROUND: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition.METHODS: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue.RESULTS: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B.CONCLUSION: Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.

KW - Adult

KW - Age of Onset

KW - Aged

KW - Aged, 80 and over

KW - Carcinoma, Renal Cell/genetics

KW - Cohort Studies

KW - Cyclin-Dependent Kinase Inhibitor p15/genetics

KW - Denmark

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Genetic Variation

KW - Humans

KW - Kidney Neoplasms/genetics

KW - Male

KW - Melanoma/genetics

KW - Microphthalmia-Associated Transcription Factor/genetics

KW - Middle Aged

KW - Mutation

KW - Neoplastic Syndromes, Hereditary/genetics

KW - Pedigree

KW - Risk Factors

KW - Tumor Suppressor Proteins/genetics

KW - Ubiquitin Thiolesterase/genetics

KW - Von Hippel-Lindau Tumor Suppressor Protein/genetics

U2 - 10.1371/journal.pone.0215725

DO - 10.1371/journal.pone.0215725

M3 - Journal article

C2 - 31034483

VL - 14

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 4

M1 - e0215725

ER -