Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

ABSTRACT Objective Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Keratocystic odontogenic tumor related to nevoid basal cell carcinoma syndrome: clinicopathological study

Aim: To assess clinicopathological features of patients with keratocystic odontogenic tumor (KCOT) associated with nevoid basal cell carcinoma syndrome (NBCCS) in a single Brazilian institution. Methods: After histopathological analyses of KCOT related to NBCCS, the medical charts of 14 patients were assessed. These patients presented a total of 31 primary and 8 recurrent KCOT. Results: Out of 14 patients, 8 presented a single KCOT, 4 showed synchronous tumors, 1 had3 metachronous lesions and another patient had 2 synchronous lesions at initial evaluation and then developed other 3 metachronous lesions. Besides the 31 primary KCOTs, 18 lesions were located in mandible and 13 in maxilla. Most tumors presented unilocular pattern and association with a tooth. Conclusions: KCOT is a frequent manifestation of NBCCS and can be its first sign, mainly in young patients. In contrast to a previously published series, most patients presented a single lesion.

Modificadores de penetrância de mutações germinativas no gene TP53 em famílias brasileiras com diagnóstico clínico da síndrome de Li-Fraumeni e Li-Fraumeni like: impacto dos polimorfismos intragênicos do TP53 e de genes / Genetic modifiers of germline TP53 mutation in brazilian families with Li-Fraumeni and Li-Fraumeni Like syndromes: impact of TP53 intragenic polymorphisms and p53 regulatory genes

A síndrome de Li-Fraumeni (LFS) e sua variante like (LFL) são associadas a mutações germinativas no gene TP53 e predispõe ao alto risco para múltiplos tumores em idade jovem. Analisamos 91 famílias LFS/LFL do sul/sudeste do Brasil para mutações germinativas e haplótipos de TP53 (PIN2, PIN3 e PEX4) e MDM2 (309T-G). A mutação R337H ocorreu em 44,4% das famílias avaliadas. Em 750 controles da região a freqüência populacional da mutação foi 0,3%. A genotipagem de oito indivíduos não relacionados R337H-positivos para 29 TAG SNPs intragênicos demonstrou o mesmo haplótipo raro estabelecendo efeito fundador para R337H. O alelo duplicado no PIN3 apresenta impacto modificador e retardo de 17,1 anos na ocorrência de tumores em famílias com mutação no TP53, enquanto o SNP309 MDM2 modula a idade dos sarcomas de partes moles.

Li-Fraumeni syndrome (LFS) and its variant like (LFL) are associated with germline mutations in the TP53 gene and predispose to a variety of cancers at an earlier age. We analyzed 91 LFS/LFL families from southern Brazil for germline mutations in TP53 and polymorphisms in TP53 (PIN2, PIN3, PEX4) and MDM2 (309T-G). The germline TP53 mutation R337H was found in 44.4% of all families included. In 750 controls from the same region, mutation prevalence was 0.3%. Genotyping of eight unrelated R337H-positive individuals for 29 intragenic TAG SNPs showed that they all shared the same rare haplotype confirming the founder effect for the mutation. Duplication of PIN3 had a modifier effect on the age of tumor onset (delay of 17.1 years) in TP53 mutation carriers whereas MDM2 SNP309 modulated age of onset for soft-tissue sarcomas.

TP53 Gene and Li-Fraumeni Syndrome

Cancer is a disease that strikes most families and itsdevastating effects bring suffering and instability to bothpatient and family. Clustering of cancers in certainfamilies is even more devastating, leading medicine tostudy its origin and ways to prevent it. Many cancersyndromes have been identified due to the repeatedoccurrence of specific tumors over a certain age-range.The rare cancer predisposition Li-Fraumeni syndrome(OMIM #151623; LFS) is transmitted in an autosomaldominant pattern, which predisposes affectedindividuals to an increased risk of developing a varietyof cancers at an early age, including childhood. The mostcharacteristic forms of cancers in LFS include soft-tissuesarcoma, breast cancers, brain tumors, and adrenocorticalcarcinomas. LFS is a dominantly inherited syndrome,frequently associated with germline mutations in theTP53 gene (OMIM #191170), which encodes protein p53.This protein regulates cell cycle, apoptosis, DNA repair,differentiation, senescence and development. Activationof p53 prevents DNA replication and cell proliferationwhen cells are subjected to stress that may disturb geneticor genomic integrity. Thus, TP53 acts as a major tumorsuppressor gene by exerting simultaneous control onmany components of the molecular mechanisms ofcarcinogenesis. Loss of p53 function may favor cancerdevelopment and explains predisposition in germlineTP53 mutation carriers. This review will discuss the maincharacteristics of TP53, its regulation, the consequencesof its inactivation in cancer, the germline TP53 mutationrelated to Li-Fraumeni syndrome and strategies forsurveillance.