Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations

Maffeis, Valeria; Cappellesso, Rocco; Nicolè, Lorenzo; Guzzardo, Vincenza; Menin, Chiara; Elefanti, Lisa; Schiavi, Francesca; Guido, Maria; Fassina, Ambrogio

doi:10.1007/s12022-019-09595-0

Cited by 9 publications

(5 citation statements)

References 43 publications

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“…Somatic BAP1 mutations are also present in other malignancies ( 52), although at lower rates: thymic carcinoma (13%), cholangiocarcinoma (7%), cutaneous melanoma (5%), basal cell carcinoma (4%), and others (ref. 74; COSMIC database, https://cancer.sanger.ac.uk/cosmic). The role of BAP1 as a two-hit tumor suppressor gene is underscored by the fact that in humans they are accompanied by monoallelic loss of 3p, or by biallelic deletions of the BAP1 locus (LOH), including broad deletions of 3p21, narrow deletions of several exons, or loss of the entire BAP1 allele (75,76).…”

Section: Somatic Bap1 Mutationsmentioning

confidence: 99%

Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

et al. 2020

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Among more than 200 BAP1 -mutant families affected by the "BAP1 cancer syndrome, " nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type-and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, BAP1 has emerged as a key regulator of gene-environment interaction.

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Section: Somatic Bap1 Mutationsmentioning

confidence: 99%

Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

et al. 2020

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“…Loss of BAP1 expression has been demonstrated in many other tumors including melanoma, mesothelioma and RCC. Maffeis et al analyzed tissues of 56 PPGLs, demonstrating the loss of BAP1 expression also in PPGLs (2/22 PGL and 12/34 PCC) [ 29 ]. Only in a few cases has an association between DTC and sporadic/genetically inherited PPGL been described.…”

Section: Discussionmentioning

confidence: 99%

A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy

Canu

Puglisi

Berchialla

et al. 2021

Cancers

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No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. <50-year category; HR 3.46, 95% CI 1.67–7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

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“…In the present study, lack of family history in four pedigrees was investigated for genes such as MDH2 , BAP1 , DLST, or SLC25A11 [ 6 , 9 , 10 , 30 ]. However, among the de novo mutation or low-penetrance inheritance, the latter is frequently associated with PPGLs [ 6 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas

Gao

Ling

et al. 2021

International Journal of Endocrinology

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Purpose. Recently, pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a CHEK2 strong association has been observed. Therefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in PPGLs. Methods. Four patients with CHEK2 mutations were recruited, as previously detected by the whole exome sequencing. Sanger sequencing was used to verify the germline mutations as well as the loss of heterozygosities (LOHs) in their somatic DNAs. Immunohistochemistry was used to analyze the expression of CHEK2 and its downstream target p53 Ser20 (phosphorylated p53). Results. The average age of studied patients was 44.25 ± 11.18 years, at the time diagnosis. One patient had multiple tumors which recurred quickly, while two patients had distant metastasis. None of the patient had any relevant family history. Four germline CHEK2 mutations were identified (c.246_260del; c.715G > A; c.1008+3A > T; and c.1111C > T). All the patients were predicted to have either pathogenic or suspected pathogenic mutations. There was no LOH of CHEK2 gene in somatic DNAs found. Additionally, neither CHEK2 proteins nor its downstream target p53 Ser20 were expressed in the tumor tissues. The inactivation of CHEK2 leads to the decrease in the p53 phosphorylation, which might promote tumorigenesis. Conclusions. For the first time, CHEK2 was identified as a susceptibility gene for PPGLs. However, the penetrance of CHEK2 gene with genotype-phenotype correlation needs to be investigated.

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Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations

Cited by 9 publications

References 43 publications

Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy

Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas

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