Somatic <i>TP53</i> Mutations Are Relatively Rare among Adrenocortical Cancers with the Frequent 17p13 Loss of Heterozygosity

Libé, Rossella; Groussin, Lionel; Tissier, Frédérique; Elie, Caroline; René-Corail, Fernande; Fratticci, Amato; Jullian, Eric; Beck‐Peccoz, Paolo; Bertagna, Xavier; Gicquel, Christine; Bertherat, Jérôme

doi:10.1158/1078-0432.ccr-06-2085

Cited by 112 publications

(99 citation statements)

References 51 publications

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“…Some alterations such as TP53 mutations or IGF-II uniparental disomy are observed in malignant tumors, whereas others like b-catenin mutations can be observed both in ACA and in ACC (19)(20)(21). The cellular and genetic alterations that lead to an activation of the cAMP pathway are usually observed in benign unilateral or bilateral cortisol-secreting tumors (22).…”

Section: Discussionmentioning

confidence: 99%

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

Vincent-Dejean

Cazabat

Groussin

et al. 2008

European Journal of Endocrinology

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Objective: The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics. Methods: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisolsecreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured. Results: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%G4 vs 100%G19, P!0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P!0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37G0.31 vs 1.00G0.20, P!0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors. Conclusion: This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.European Journal of Endocrinology 158 829-839

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Section: Discussionmentioning

confidence: 99%

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

Vincent-Dejean

Cazabat

Groussin

et al. 2008

European Journal of Endocrinology

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“…Somatic TP53 mutations are found in 25-30% of sporadic ACC, but not in ACA. Positive p53 immunohistochemistry is well correlated with the presence of TP53 mutation in ACC [26]. In particular, ACC harboring TP53 mutation were associated with a more advanced stage of tumor progression and had a shorter disease-free survival [25].…”

Section: P53mentioning

confidence: 98%

The Weiss Score and Beyond—Histopathology for Adrenocortical Carcinoma

et al. 2011

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The pathological diagnosis of adrenocortical carcinoma (ACC) is still challenging for its rarity and the presence of special variants (pediatric, oncocytic, myxoid, and sarcomatoid). It is based on the recognition at light microscopy of at least three among nine morphological parameters, according to the Weiss scoring system, which has been introduced 27 years ago and nowadays is the most widely employed. Nevertheless, the diagnostic performance of this system is very high but does not reach a sensitivity and specificity of 100%, its diagnostic applicability is potentially low among non-expert pathologists, and a group of borderline cases with only one or two criteria exist of uncertain behavior. Moreover, it is scarcely reproducible in the ACC morphological variants. In fact, specifically for the pure oncocytic neoplasms that seem to have a better prognosis in comparison to the conventional ACCs, a modified system (the Lin-Weiss-Bisceglia) has been proposed. With the aim to simplify the ACC diagnosis, 2 years ago, the "reticulin" diagnostic algorithm has been proposed, based on the observation that the tumoral reticulin framework (highlighted by reticulin silver-based histochemical staining) is consistently disrupted in malignant cases but only in a small subset of benign cases. Following this algorithm, in the presence of reticulin alterations, malignancy is further defined through the identification of at least one of the following parameters: necrosis, high mitotic rate, and venous invasion. As a complement to the morphological approach, some immunohistochemical markers (such as steroidogenic factor 1) have been proposed as diagnostic and prognostic adjuncts but still lack wide clinical validation.

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“…Of note is the presence of some of these histopathological criteria in both tumors presented by the child (Table 1), however, the tumors' weights and sizes are beneath these ranges. Among various clinical parameters that have been shown to impact adrenocortical carcinoma prognosis, tumor staging has been demonstrated as one of the most important (13). The staging system for adrenocortical carcinomas depends upon tumor size, nodal involve-ment, invasion of adjacent organs, and presence of distant metastasis (9).…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

Lima

Lerário

Alencar

et al. 2011

Arq Bras Endocrinol Metab

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SUMMARYThe occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors.In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient. Arq Bras Endocrinol Metab. 2011;55(1):72-7 SUMÁRIO A ocorrência de carcinomas adrenocorticais metacrônicos é raramente relatada. Descrevemos o caso de uma criança portadora de tumor adrenocortical virilizante metacrônico que, apesar das inúmeras metástases, apresentou uma longa sobrevida (15 anos). Analisamos nesse tumor a expressão gênica de IGF2, IGF1R e FGFR4 e avaliamos a presença da mutação germinativa R337H no p53 e mutação somática no gene CTNNB1. O gene IGF2 foi hiperexpresso nos tumores adrenocorticais esquerdo (Weiss 5) e direito (Weiss 7). Os níveis de expressão de IGF1R foram maiores no tumor direito. Hiperexpressão do gene FGFR4 também foi observada no tumor adrenocortical direito. Esse paciente é portador da mutação germinativa R337H no p53, e perda de heterozigose (LOH) foi observada em ambos os tumores. Não foram encontradas mutações no gene CTNNB1 nos tumores. Em conclusão, demonstramos neste caso a hiperexpressão de vias moleculares de crescimento, que são mecanismos previamente relacionados à tumorigê-nese adrenocortical. Além disso, não encontramos mutações somáticas no gene CTNNB1, que é um marcador molecular de mau prognóstico em adultos e poderia estar relacionado à longa sobrevida desse paciente. Arq Bras Endocrinol Metab. 2011;55(1):72-7

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Somatic TP53 Mutations Are Relatively Rare among Adrenocortical Cancers with the Frequent 17p13 Loss of Heterozygosity

Cited by 112 publications

References 51 publications

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

The Weiss Score and Beyond—Histopathology for Adrenocortical Carcinoma

Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

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