Genetic Changes in Human Adrenocortical Carcinomas

Yano, Tomomi; Linehan, Marston; Anglard, Patrick; Mi, Lerman; Ln, Daniel; Ca, Stein; Cn, Robertson; LaRocca, Renato; Zbar, B.

doi:10.1093/jnci/81.7.518

Cited by 127 publications

(67 citation statements)

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“…This result was supported by the finding of a consistent loss of heterozygosity (LOH) at chromosomal locus 17p in adrenal carcinomas but not in adrenal adenomas. Allelic losses at the 17p locus were shown in all adrenocortical carcinomas, whereas LOH at 11p and 13q loci were found in only half of the malignant tumors (24).…”

Section: Discussionmentioning

confidence: 94%

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors

Sachse

Shao

Rico

et al. 1997

European Journal of Endocrinology

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Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisolproducing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T 573 →C) in cortisol-producing tumors needs to be further evaluated.

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Section: Discussionmentioning

confidence: 94%

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors

Sachse

Shao

Rico

et al. 1997

European Journal of Endocrinology

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“…TP53 (17q13) (hCHK2) Soft tissue sarcoma, breast cancers, brain tumours, leukaemia, ACC TP53 germline mutation in paediatric ACC (32,33) TP53 somatic mutations in sporadic ACC (37,38) 17p13 LOH in sporadic ACC (26,28) Multiple endocrine neoplasia type 1 (MEN 1) Pituitary tumours were initially reported to have a monoclonal origin (7, 8), but Farrell & Clayton (9) suggested a different clonal composition for these endocrine tumours. Indeed, although pituitary tumours are generally benign adenomas, they can recur and grow after initial surgery.…”

Section: Li-fraumeni Syndrome (Lfs)mentioning

confidence: 99%

“…Studies using microsatellite markers have demonstrated high percentages of loss of heterozygosity (LOH)/allelic imbalance at 11q13 (100%) (23)(24)(25) and 2p16 (92%) (23) in carcinomas. Moreover, LOH of the 17p13 locus (26,27) has been reported to be highly specific to malignant tumours and to be of prognostic value for the recurrence of localized tumours (28).…”

Section: The Importance Of Genetic Alterations In Sporadic Actsmentioning

confidence: 99%

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Molecular genetics of adrenocortical tumours, from familial to sporadic diseases

2005

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Adrenal masses can be detected in up to 4% of the population, and are mostly of adrenocortical origin. Adrenocortical tumours (ACTs) may be responsible for excess steroid production and, in the case of adrenocortical cancers, for morbidity or mortality due to tumour growth. Our understanding of the pathogenesis of ACTs is more limited than that for other tumours. However, studies of the genetics of ACTs have led to major advances in this field in the last decade. The identification of germline molecular defects in the hereditary syndrome responsible for ACTs has facilitated progress. Indeed, similar molecular defects have since been identified as somatic alterations in sporadic tumours. The familial diseases concerned are Li-Fraumeni syndrome, which may be due to germline mutation of the tumour-suppressor gene TP53 and Beckwith -Wiedemann syndrome, which is caused by dysregulation of the imprinted IGF-II locus at 11p15. ACTs also occur in type 1 multiple endocrine neoplasia (MEN 1), which is characterized by a germline mutation of the menin gene. Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) has been observed in Carney complex patients presenting inactivating germline PRKAR1A mutations. Interestingly, allelic losses at 17p13 and 11p15 have been demonstrated in sporadic adrenocortical cancer and somatic PRKAR1A mutations have been found in secreting adrenocortical adenomas. More rarely, mutations in Gs protein (gsp) and the gene for ACTH receptor have been observed in ACTs. The genetics of another group of adrenal diseases that can lead to adrenal nodular hyperplasia -congenital adrenal hyperplasia (CAH) and glucocorticoid-remediable aldosteronism (GRA) -have also been studied extensively. This review summarizes recent advances in the genetics of ACTs, highlighting both improvements in our understanding of the pathophysiology and the diagnosis of these tumours.

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“…The rarity of the tumour and the low level of proliferation have made classical cytogenetic analysis difficult. Demonstration of allelic loss on chromosomes 11p, 13q and 17p (Henry et al, 1989;Yano et al, 1989) suggest that genes at these loci may have a role in pathogenesis. Familial adrenocortical cancer occurs in Beckwith-Wiedemann syndrome linked to 11p 15.5, and now known to be associated with paternal disomy for the insulin-growth factor-II (IGF-II) gene (Weksberg et al, 1993).…”

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confidence: 99%

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

et al. 1999

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SummaryThe investigation of chromosomal aberrations in adrenocortical tumours has been limited by the difficulties of applying classical cytogenetics to tumours with low levels of proliferation. We have therefore applied the technique of interphase cytogenetics to paraffin-embedded archival specimens of 14 adrenocortical adenomas and 13 carcinomas. Hybridizations were performed using centromere-specific probes to chromosomes 3, 4, 9, 17, 18 and X, which have been shown to be altered in other types of tumours. Chromosomal imbalance was defined on the basis of changes in both chromosome index (CI) and signal distribution (SD). Where only one of these was altered, this was classified as a tendency to gain or loss. On the basis of the analysis of optimal hybridizations, carcinomas showed gains in all chromosomes studied, five of nine showing gains in multiple chromosomes. Gains were most common in chromosomes 3, 9 and, in particular X, eight of 11 showing gain, and one a tendency to gain. Chromosomal gain was seen less commonly in adenomas, but again chromosomes 3, 9 and X were involved. Losses were infrequent, only one carcinoma showing loss of chromosome 18, and adenomas showing a tendency to loss of chromosomes 4 (two cases), 17 (one case) and 18 (two cases). Our data suggest that changes in chromosomes 3, 9 and X are early events in adrenocortical tumorigenesis, and that there is increasing chromosomal instability with tumour progression.

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Genetic Changes in Human Adrenocortical Carcinomas

Cited by 127 publications

References 0 publications

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors

Molecular genetics of adrenocortical tumours, from familial to sporadic diseases

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

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