Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors.
BACKGROUND
Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumors (GISTs) and pulmonary chondromas. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC, and SDHD are found in PGLs, gain-of-function mutations of c-kit (KIT), and platelet-derived growth factor receptor A (PDGFRA) in GISTs.


OBJECTIVE
Our objective was to investigate the possibility that patients with CT and/or their tumors may harbor mutations of the SDHB, SDHC, SDHD, KIT, and PDGFRA genes and identify any other genetic alterations in CT tumors.


METHODS
Three males and 34 females with CT were studied retrospectively. We sequenced the stated genes and performed comparative genomic hybridization on a total of 41 tumors.


RESULTS
No patient had coding sequence mutations of the investigated genes. Comparative genomic hybridization revealed a number of DNA copy number changes: losses dominated among benign lesions, there were an equal number of gains and losses in malignant lesions, and the average number of alterations in malignant tumors was higher compared with benign lesions. The most frequent and greatest contiguous change was 1q12-q21 deletion, a region that harbors the SDHC gene. Another frequent change was loss of 1p. Allelic losses of 1p and 1q were confirmed by fluorescent in situ hybridization and loss-of-heterozygosity studies.


CONCLUSIONS
We conclude that CT is not due to SDH-inactivating or KIT- and PDGFRA-activating mutations. GISTs and PGLs in CT are associated with chromosome 1 and other changes that appear to participate in tumor progression and point to their common genetic cause.
Matyakhina
Ludmila
L
Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Bei
Thalia A
TA
McWhinney
Sarah R
SR
Pasini
Barbara
B
Cameron
Silke
S
Gunawan
Bastian
B
Stergiopoulos
Sotirios G
SG
Boikos
Sosipatros
S
Muchow
Michael
M
Dutra
Amalia
A
Pak
Evgenia
E
Campo
Elias
E
Cid
Maria C
MC
Gomez
Fulgencio
F
Gaillard
Rolf C
RC
Assie
Guillaume
G
Füzesi
Laszlo
L
Baysal
Bora E
BE
Eng
Charis
C
Carney
J Aidan
JA
Stratakis
Constantine A
CA
D000293:Adolescent; D000328:Adult; D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D018628:Gene Dosage; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009693:Nucleic Acid Hybridization; D010235:Paraganglioma / Q000235:genetics*; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000235:genetics; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D013385:Succinate Dehydrogenase