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Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.
- Source :
-
Cancer [Cancer] 2020 Aug 15; Vol. 126 (16), pp. 3657-3666. Date of Electronic Publication: 2020 May 15. - Publication Year :
- 2020
-
Abstract
- Background: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance.<br />Methods: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.<br />Results: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10 <superscript>-3</superscript> (1 in 393) and 1.20 × 10 <superscript>-3</superscript> (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%.<br />Conclusions: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.<br /> (© 2020 American Cancer Society.)
- Subjects :
- Adult
Exome genetics
Female
Gene Frequency
Germ-Line Mutation genetics
Heterozygote
Humans
Kidney metabolism
Kidney pathology
Kidney Neoplasms epidemiology
Kidney Neoplasms etiology
Kidney Neoplasms pathology
Leiomyomatosis complications
Leiomyomatosis epidemiology
Leiomyomatosis pathology
Male
Middle Aged
Neoplastic Syndromes, Hereditary complications
Neoplastic Syndromes, Hereditary epidemiology
Neoplastic Syndromes, Hereditary pathology
Risk Factors
Skin Neoplasms complications
Skin Neoplasms epidemiology
Skin Neoplasms pathology
Uterine Neoplasms complications
Uterine Neoplasms epidemiology
Uterine Neoplasms pathology
Fumarate Hydratase genetics
Genetic Predisposition to Disease
Kidney Neoplasms genetics
Leiomyomatosis genetics
Neoplastic Syndromes, Hereditary genetics
Skin Neoplasms genetics
Uterine Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0142
- Volume :
- 126
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 32413184
- Full Text :
- https://doi.org/10.1002/cncr.32914