Date Published: April 29, 2019
Publisher: Public Library of Science
Author(s): Maria Bejerholm Christensen, Karin Wadt, Uffe Birk Jensen, Charlotte Kvist Lautrup, Anders Bojesen, Lotte Nylandsted Krogh, Thomas van Overeem Hansen, Anne-Marie Gerdes, Amanda Ewart Toland.
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.
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.
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.
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.
Renal cell carcinomas (RCCs) are the most frequent malignancies of the kidneys and comprise different subtypes with highly heterogeneous histopathology: 70–75% are clear cell (ccRCC), 10–16% are papillary (type 1 or 2), 5% are chromophobe, and the remaining 10% consists of other subtypes such as collecting duct and medullary tumors . In Denmark, RCC represents 2–3% of all cancers with an average incidence of 825 cases/year for 2011–2015. Cancer detection at an early stage with identification of small and localized tumors decreases morbidity and thus presymptomatic screening and surveillance of patients with high risk of RCC development is likely to decrease RCC mortality [3,4].
We found three VUS’s in BAP1 and two VUS’s in VHL. Forty-six families in the current study, including thirteen families with melanoma, have been screened for the known E318K-variant in MITF, but the variant has only been found in one family, which has previously been published . No variants were found in CDKN2B. Our cohort was characterized by a surplus of men, and most patients were overweight and exposed to smoking, all of which are known risk factors for RCC.