title: Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer.
abstract: Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Seballos
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Shireen
authors.initials: S
authors.lastname: Ganapathi
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gurin
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fletcher
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kloos
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine InstituteLerner Research InstituteTaussig Cancer InstituteStanley Shalom Zielony Nursing InstituteCleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USADivision of Medical OncologyNational Cancer Center, Singapore 169610, SingaporeDivisions of Human GeneticsEndocrinology and MetabolismDepartment of MedicineComprehensive Cancer CenterArthur G. James Cancer Hospital and Richard G. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USADepartments of Genetics and Genome SciencesEpidemiology and BiostatisticsCASE Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio 44116, USA Genomic Medicine Ins
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics; D002291:Carcinoma, Papillary; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D013385:Succinate Dehydrogenase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: SDHx; gene expression; papillary thyroid cancer; variant