Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes

Ying Ni, Kevin M. Zbuk, Tammy Sadler, A. Patócs, Glenn Lobo, Emily Edelman, Petra Platzer, Mohammed S. Orloff, Kristin A. Waite, Charis Eng

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p <0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p <0.001), thyroid (5/10 versus 15/106, p <0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

Original languageEnglish
Pages (from-to)261-268
Number of pages8
JournalAmerican Journal of Human Genetics
Volume83
Issue number2
DOIs
Publication statusPublished - Aug 8 2008

Fingerprint

Multiple Hamartoma Syndrome
Succinate Dehydrogenase
Germ-Line Mutation
Mutation
Genes
Kidney Neoplasms
Breast Neoplasms
Thyroid Neoplasms
Thyroid Gland
Cowden-Like Syndrome
Kidney
Paraganglioma
Neoplasms
Pheochromocytoma
Superoxide Dismutase
Breast
Phosphorylation

ASJC Scopus subject areas

  • Genetics

Cite this

Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes. / Ni, Ying; Zbuk, Kevin M.; Sadler, Tammy; Patócs, A.; Lobo, Glenn; Edelman, Emily; Platzer, Petra; Orloff, Mohammed S.; Waite, Kristin A.; Eng, Charis.

In: American Journal of Human Genetics, Vol. 83, No. 2, 08.08.2008, p. 261-268.

Research output: Contribution to journalArticle

Ni, Y, Zbuk, KM, Sadler, T, Patócs, A, Lobo, G, Edelman, E, Platzer, P, Orloff, MS, Waite, KA & Eng, C 2008, 'Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes', American Journal of Human Genetics, vol. 83, no. 2, pp. 261-268. https://doi.org/10.1016/j.ajhg.2008.07.011
Ni, Ying ; Zbuk, Kevin M. ; Sadler, Tammy ; Patócs, A. ; Lobo, Glenn ; Edelman, Emily ; Platzer, Petra ; Orloff, Mohammed S. ; Waite, Kristin A. ; Eng, Charis. / Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes. In: American Journal of Human Genetics. 2008 ; Vol. 83, No. 2. pp. 261-268.
@article{fbdcf845405b41cd8f9f7b485c433224,
title = "Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes",
abstract = "Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20{\%}) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5{\%}) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p <0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p <0.001), thyroid (5/10 versus 15/106, p <0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.",
author = "Ying Ni and Zbuk, {Kevin M.} and Tammy Sadler and A. Pat{\'o}cs and Glenn Lobo and Emily Edelman and Petra Platzer and Orloff, {Mohammed S.} and Waite, {Kristin A.} and Charis Eng",
year = "2008",
month = "8",
day = "8",
doi = "10.1016/j.ajhg.2008.07.011",
language = "English",
volume = "83",
pages = "261--268",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes

AU - Ni, Ying

AU - Zbuk, Kevin M.

AU - Sadler, Tammy

AU - Patócs, A.

AU - Lobo, Glenn

AU - Edelman, Emily

AU - Platzer, Petra

AU - Orloff, Mohammed S.

AU - Waite, Kristin A.

AU - Eng, Charis

PY - 2008/8/8

Y1 - 2008/8/8

N2 - Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p <0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p <0.001), thyroid (5/10 versus 15/106, p <0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

AB - Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p <0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p <0.001), thyroid (5/10 versus 15/106, p <0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

UR - http://www.scopus.com/inward/record.url?scp=48249113935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48249113935&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2008.07.011

DO - 10.1016/j.ajhg.2008.07.011

M3 - Article

VL - 83

SP - 261

EP - 268

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -