Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex)

Constantine A. Stratakis, Robert Brian Jenkins, Elon Pras, Constantine S. Mitsiadis, Sandra B. Raff, Paul G. Stalboerger, Constantine Tsigos, J. Aidan Carney, George P. Chrousos

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD; n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

Original languageEnglish (US)
Pages (from-to)3607-3614
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume81
Issue number10
DOIs
StatePublished - 1996

Fingerprint

Carney Complex
Skin Pigmentation
Chromosomes
Myxoma
Cytogenetics
Microsatellite Repeats
Tumors
Skin
Cells
Genes
Tissue
Neoplasms
Microsatellite Instability
Tumor Cell Line
Adenoma
Lentigo
Dominant Genes
Cell Line
Spindle Apparatus
Chromosomes, Human, Pair 3

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex). / Stratakis, Constantine A.; Jenkins, Robert Brian; Pras, Elon; Mitsiadis, Constantine S.; Raff, Sandra B.; Stalboerger, Paul G.; Tsigos, Constantine; Carney, J. Aidan; Chrousos, George P.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 81, No. 10, 1996, p. 3607-3614.

Research output: Contribution to journalArticle

Stratakis, Constantine A. ; Jenkins, Robert Brian ; Pras, Elon ; Mitsiadis, Constantine S. ; Raff, Sandra B. ; Stalboerger, Paul G. ; Tsigos, Constantine ; Carney, J. Aidan ; Chrousos, George P. / Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex). In: Journal of Clinical Endocrinology and Metabolism. 1996 ; Vol. 81, No. 10. pp. 3607-3614.
@article{9ec888590e2e4524926bd24f820381f6,
title = "Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex)",
abstract = "Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD; n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49{\%} and 26{\%}, respectively), deletions of both alleles (DEL; 10{\%}), and microsatellite length instability (15{\%}). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40{\%} of the informative loci tested (73{\%}, 59{\%}, 47{\%}, 46{\%}, and 44{\%}, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10{\%}). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.",
author = "Stratakis, {Constantine A.} and Jenkins, {Robert Brian} and Elon Pras and Mitsiadis, {Constantine S.} and Raff, {Sandra B.} and Stalboerger, {Paul G.} and Constantine Tsigos and Carney, {J. Aidan} and Chrousos, {George P.}",
year = "1996",
doi = "10.1210/jc.81.10.3607",
language = "English (US)",
volume = "81",
pages = "3607--3614",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "10",

}

TY - JOUR

T1 - Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex)

AU - Stratakis, Constantine A.

AU - Jenkins, Robert Brian

AU - Pras, Elon

AU - Mitsiadis, Constantine S.

AU - Raff, Sandra B.

AU - Stalboerger, Paul G.

AU - Tsigos, Constantine

AU - Carney, J. Aidan

AU - Chrousos, George P.

PY - 1996

Y1 - 1996

N2 - Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD; n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

AB - Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD; n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

UR - http://www.scopus.com/inward/record.url?scp=0029838757&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029838757&partnerID=8YFLogxK

U2 - 10.1210/jc.81.10.3607

DO - 10.1210/jc.81.10.3607

M3 - Article

C2 - 8855810

AN - SCOPUS:0029838757

VL - 81

SP - 3607

EP - 3614

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 10

ER -