Recent advances in the pathogenesis of adrenocortical tumours

Gicquel, Christine; Bertagna, Xavier; Bouc, Yves Le

doi:10.1530/eje.0.1330133

Cited by 62 publications

(47 citation statements)

References 71 publications

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“…Most sporadic adrenal tumors are monoclonal, suggesting that a somatic genetic defect occurs early during tumorigenesis (4). Somatic mutations of the tumor suppressor gene TP53 were initially reported, mostly in adrenal carcinomas (5).…”

Section: Introductionmentioning

confidence: 99%

Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Tissier¹,

Cavard

Groussin³

et al. 2005

Cancer Research

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Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of B-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the b-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal B-catenin accumulation and most were point mutations altering the Ser 45 of exon 3 (in the consensus GSK3-B/CK1 phosphorylation site). Functional studies showed that the activating Ser 45 b-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor-dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. b-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, Bcatenin alterations are more frequent in nonfunctioning tumors, suggesting that B-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of Bcatenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available. (Cancer Res 2005; 65(17): 7622-7)

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Section: Introductionmentioning

confidence: 99%

Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Tissier¹,

Cavard

Groussin³

et al. 2005

Cancer Research

Self Cite

434

351

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“…Following the rearrangement event, the disappearance of this regulator would lead to the overexpression of the gene. The disappearance of a negative regulator of IGF2 gene expression has been proposed by others to explain the very high levels of IGF2 transcripts in some tumours (Fidler et al, 1992;Gicquel et al, 1995). This, in addition to loss of parental imprinting or loss of heterozygocity, might represent a novel mechanism of IGF2 gene overexpression.…”

Section: Introductionmentioning

confidence: 92%

Cloning of breakpoints in and downstream the IGF2 gene that are associated with overexpression of IGF2 transcripts in colorectal tumours

et al. 1999

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The human IGF2 gene belongs to a group of imprinted genes clustered on the short arm of chromosome 11, band p15.5. It contains 9 exons and spans over 30 kb. IGF2 mRNA overexpression has been reported in human tumours and in some inherited growth disorders. It was recently demonstrated that IGF2 mRNA overexpression contributes to tumour progression and that loss of parental imprinting as well as altered transcription factors are contributing to this overexpression. We have reported structural alterations in the 3' region of the IGF2 gene in two colorectal tumours that overexpressed the IGF2 transcript by 200-and 800-fold. We cloned by the vectorette-PCR strategy, genomic DNA fragments containing the breakpoints from these tumours. The sequencing of these fragments positioned the breakpoint 2 kb downstream the IGF2 gene in one tumour, and in exon 9 in the second. Both breakpoints occurred in regions containing repetitive elements: a TGGA repeat we have identi®ed downstream the gene, and the (CA)n repetition in exon 9. We hypothesize that a negative regulatory element, located downstream the IGF2 gene, has been deleted following these structural alterations and leads to IGF2 gene overexpression.

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“…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%

“…The IGF system is involved in the development and maintenance of differentiated adrenocortical functions and its role has been largely documented in ACTs (6,27,28). Many studies have demonstrated that IGF-II is often strongly overexpressed in malignant ACTs, with such overexpression observed in approximately 90% of ACCs (61 -63).…”

Section: Igf-ii and 11p15 Alterationsmentioning

confidence: 99%

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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Recent advances in the pathogenesis of adrenocortical tumours

Cited by 62 publications

References 71 publications

Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Cloning of breakpoints in and downstream the IGF2 gene that are associated with overexpression of IGF2 transcripts in colorectal tumours

Molecular genetics of adrenocortical tumours, from familial to sporadic diseases

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