RB1 mutations and second primary malignancies after hereditary retinoblastoma.
Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199 survivors of hereditary retinoblastoma with a documented RB1 germline mutation diagnosed between 1905 and 2005. In total, 44 hereditary retinoblastoma survivors developed a second primary malignancy after a median follow-up of 30.2 years (range 1.33-76.0). A significantly increased risk of second primary malignancy was observed among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations (hazard ratio (HR) = 3.53; [95% confidence interval (CI) = 1.82-6.84]; P = .000), and there was a significantly lower risk for subjects with a low penetrance mutation (HR = .19; [95% CI = .05-.81]; P = .025). Our findings suggest a genotype-phenotype correlation for second primary cancers of retinoblastoma survivors and may impact on long-term surveillance protocols of patients with hereditary retinoblastoma, if confirmed by future studies.
Department of Clinical Genetics, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. cj.dommering@vumc.nl
Charlotte J
CJ
Dommering
Tamara
T
Marees
Annemarie H
AH
van der Hout
Saskia M
SM
Imhof
Hanne
H
Meijers-Heijboer
Peter J
PJ
Ringens
Flora E
FE
van Leeuwen
Annette C
AC
Moll
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D018389:Codon, Nonsense; D015331:Cohort Studies; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000401:mortality; D009426:Netherlands; D016016:Proportional Hazards Models; D019572:Retinal Neoplasms / Q000235:genetics* / Q000401:mortality; D012175:Retinoblastoma / Q000235:genetics* / Q000401:mortality; D016160:Retinoblastoma Protein / Q000235:genetics*; D012189:Retrospective Studies; D017741:Survivors; D055815:Young Adult
D018389:Codon, Nonsense; D016160:Retinoblastoma Protein