Detailed genomic characterization identifies high heterogeneity and histotype-specific genomic profiles in adrenocortical carcinomas

Abstract

Molecular characterization of adrenocortical carcinoma has been recently established, but the correlation between molecular profiles and clinical and pathological characteristics is still poorly defined with no data available about genetic heterogeneity along disease progression. In this scenario, a detailed molecular profile was correlated with clinical and pathological characteristics in adrenocortical carcinoma patients to identify potentially novel biomarkers. Targeted next-generation sequencing and copy number variation analyses for 18 most frequently altered genes in adrenocortical carcinoma were assessed on 62 adult cases (including 10 with matched primary and metastatic/recurrence samples) and results correlated with major clinical and pathological characteristics of tumors. A total of 433 somatic deleterious genetic alterations (328 gene mutations and 105 copy number variations) were identified in 57/62 cases, five resulted wild type for all genes tested. TERT, CDK4, ZNRF3,and RB1 were altered in more than 30% of cases. Among histological variants genotypes were significantly different. Lowest mutation burden was found in the oncocytic type (p = 0.006), whereas the highest with a prevalence of RB1 (p = 0.001) and CDK4 (p = 0.002) was found in the conventional and myxoid ones, respectively. None of the 10 cases with matched samples showed a stable genotype along tumor progression, although allelic frequencies or percentages of altered nuclei at fluorescence in situ hybridization were in most cases similar among different tumor samples for genes that were stable along tumor progression. Among individual genes, an altered p53/Rb1 pathway was the strongest adverse molecular signature, being associated with high Ki-67 index, high tumor stage, aggressive disease status, and shorter disease-free survival. The genomic signature in adrenocortical carcinoma is changing along tumor progression and is associated with specific clinical and pathological features, including histological variant and prognosis.

Metastatic Adrenal Cortical Carcinoma Responding to Octreotide: A Case Report

“…A recent study also proposed a combination of molecular, clinical, and histopathological parameters, including number of somatic mutations, alterations in Wnt/β‐catenin and p53 pathways, promoter regions methylation pattern, tumor stage, grading, resection status, age, symptoms caused by steroid autonomous secretion, or tumor mass to improve prognostication, in patients with advanced ACC. However, the authors found that none of the single molecular events showed a significant predictive role for response to mitotane monotherapy, etoposide‐doxorubicin‐cisplatin, gemcitabine plus capecitabine, and/or streptozotocin . Our next‐generation sequencing‐based ctDNA also failed to identify any mutations because no circulating tumor DNA was detected.…”

Pathobiology and genetics of adrenocortical carcinoma

“…A recent study has highlighted the potential diagnostic and prognostic benefit of assessing chromosomal alterations by correlating mutations and copy number variations to ACC histotype. A lower mutation burden was identified in oncocytic tumours and the highest in the conventional and myxoid ACCs (Vatrano et al 2018).…”

Análise do perfil de expressão do miR-483-3p e do miR-630 em tumores adrenocorticais e o efeito dessa modulação na tumorigênese da adrenal

“…Estudos têm sido feitos, com grandes esforços, para melhorar o tratamento e qualidade de vida dos pacientes; no entanto, o prognóstico ainda permanece limitado, visto que o CAC é uma doença muito heterogênea e abriga uma diversidade de variantes morfológicas, clínicas e genéticas, que auxiliam no valor prognóstico (VATRANO; VOLANTE; GIORCELLI et al, 2018;. Até agora, a maioria dos dados moleculares disponíveis sobre o CAC está restrita à expressão gênica, array-CGH ou perfil de metiloma e comparam carcinomas com o equivalente benigno, os adenomas (VATRANO; VOLANTE; GIORCELLI et al, 2018).…”

“…O papel desses genes na progressão tumoral ainda é controverso e nenhuma dessas alterações demonstrou ser marcador de prognóstico ou preditivo para direcionar o tratamento, visto que a assinatura genômica do TAC é altamente instável ao longo da progressão do tumor. (VATRANO;GIORCELLI et al, 2018). Portanto, há uma grande necessidade de maiores investigações para definir possíveis biomarcadores que possam ter um impacto positivo na clínica (VATRANO;GIORCELLI et al, 2018).…”

“…(VATRANO;GIORCELLI et al, 2018). Portanto, há uma grande necessidade de maiores investigações para definir possíveis biomarcadores que possam ter um impacto positivo na clínica (VATRANO;GIORCELLI et al, 2018).…”