Brian Shuch1,2, Shantao Li3,4,5, Harvey Risch6, Ranjit S Bindra7, Patrick D McGillivray3, Mark Gerstein3,4,5. 1. Department of Urology and Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut. 2. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 3. Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut. 4. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut. 5. Department of Computer Science, Yale University, New Haven, Connecticut. 6. Division of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. 7. Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
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. 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. RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10-3 (1 in 393) and 1.20 × 10-3 (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%. 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.
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. 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. RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10-3 (1 in 393) and 1.20 × 10-3 (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%. 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.
Authors: Jack P Gleeson; Ines Nikolovski; Renzo Dinatale; Mark Zucker; Andrea Knezevic; Sujata Patil; Yasser Ged; Ritesh R Kotecha; Natalie Shapnik; Samuel Murray; Paul Russo; Jonathan Coleman; Chung Han Lee; Zsofia K Stadler; A Ari Hakimi; Darren R Feldman; Robert J Motzer; Ed Reznik; Martin H Voss; Ying-Bei Chen; Maria I Carlo Journal: Clin Cancer Res Date: 2021-03-03 Impact factor: 12.531
Authors: Eric Lu; Kathryn E Hatchell; Sarah M Nielsen; Edward D Esplin; Karen Ouyang; Keith Nykamp; Shirin Zavoshi; Shantao Li; Liying Zhang; Blake R Wilde; Heather R Christofk; Paul C Boutros; Brian Shuch Journal: Cancer Date: 2021-11-01 Impact factor: 6.921