title: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management.
abstract: OBJECTIVE
  Approximately 5% to 8% of renal cell carcinoma (RCC) is hereditary. No guidelines exist for patient selection for RCC germline mutation testing. We evaluate how age of onset could indicate the need for germline mutation testing for detection of inherited forms of kidney cancer.
  
  
  METHODS
  We analyzed the age distribution of RCC cases in the SEER-17 program and in our institutional hereditary kidney cancer population. The age distributions were compared by sex, race, histology, and hereditary cancer syndrome. Models were established to evaluate the specific age thresholds for genetic testing.
  
  
  RESULTS
  The median age of patients with RCC in SEER-17 was 64 years, with the distribution closely approaching normalcy. Statistical differences were observed by race, sex, and subtype (P < .05). The bottom decile cutoff was ≤ 46 years of age and slightly differed by sex, race, and histology. The mean and median ages at presentation of 608 patients with hereditary kidney cancer were 39.3 years and 37 years, respectively. Although age varied by specific syndrome, 70% of these cases were found to lie at or below the bottom age decile. Modeling age-based genetic testing thresholds demonstrated that the 10th percentile maximized sensitivity and specificity.
  
  
  CONCLUSIONS
  Early age of onset might be a sign of hereditary RCC. Even in the absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should trigger consideration for genetic counseling/germline mutation testing and may serve as a useful cutoff when establishing genetic testing guidelines.
authors.affiliation: All authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Brian
authors.initials: B
authors.lastname: Shuch
authors.forename: Srinivas
authors.initials: S
authors.lastname: Vourganti
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Lindsay
authors.initials: L
authors.lastname: Middleton
authors.forename: James
authors.initials: J
authors.lastname: Peterson
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Adam R
authors.initials: AR
authors.lastname: Metwalli
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D015994:Incidence; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D018579:Patient Selection; D010375:Pedigree; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D018426:SEER Program; D014481:United States / Q000453:epidemiology; D055815:Young Adult