title: Rare inactivating PDE11A variants associated with testicular germ cell tumors.
abstract: Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Pathak
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Bass
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Loud
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: McGlynn
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.affiliation: Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAProgram on Developmental Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USACancer Genomics Research LaboratoryDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USAPerelman School of MedicineAbramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USAGenetic Epidemiology BranchHormonal and Reproductive Epidemiology BranchDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 6E422, Rockville, Maryland 20850, USA mirabellol@mail.nih.gov.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D000242:Cyclic AMP / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009373:Neoplasms, Germ Cell and Embryonal / Q000201:enzymology / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012306:Risk; D013736:Testicular Neoplasms / Q000201:enzymology / Q000235:genetics*; D014162:Transfection; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human
keywords: PDE11A; cAMP; rare variants; risk; testicular cancer