Adrenocortical Carcinoma (ACC) Panel

About Adrenocortical Carcinoma  

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, characterized by the development of cancer in the adrenal cortex. Symptoms of ACC vary and often do not include typical symptoms of cancer such as cachexia and night sweats. Approximately 40% to 60% of patients present with symptoms of hormonal excess, ~30% present with nonspecific symptoms due to local tumor growth, such as abdominal pain or fullness, and ~20% to 30% are diagnosed via imaging studies performed for unrelated medical issues.^1,2 ACC often presents as part of other disorders. ACC often occurs in people with Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), multiple endocrine neoplasia type I (MEN1), and Lynch syndrome.^2,3 ACC account for approximately 0.2% of childhood cancers, and occurs more frequently in females than in males (approximately 1.5 to 2.5 times more often).^2,3 Most ACC cases are sporadic (but autosomal dominant inheritance has been documented) and arise due to variants in the TP53 gene.^1-3 One of the most common germline TP53 variants reported is R337H, which exists in approximately 0.3% of the population of southeastern Brazil due to a founder effect.⁵ Consequently, the incidence of ACC in southeastern Brazil is approximately 10- to 15-fold higher than other populations, estimated to be approximately 4.8:1,000,000 in adults and 6.4:1,000,000 in children below the age of ten.^2,3,6 This R337H variant frequently segregates with tumor development in LFS, although penetrance is incomplete.⁴ The diagnostic yield of this panel will vary based on the clinical phenotype of the patient and is expected to be approximately 80%.^2,4 

The analytical sensitivity of the PGxome platform has been validated at >99% for single nucleotide variants, >95% for indels <49 bp, and >99% for CNV ≥3 exons in size. Sensitivity is reduced in regions with repetitive elements or paralogy.  The analytical sensitivity of the PGnome platform has been validated at >99% for sequence variants and >99% for structural variants (SV) 1kb-10Mb in size. Sensitivity is reduced in regions with repetitive elements or paralogy. 

PGxome® platform: Capture and amplification based Next Generation Sequencing (NGS) is used to sequence the coding regions of nearly all genes and immediate flanking non-coding DNA (± 10 bp) in all available transcripts along with other non-coding regions harboring known disease-causing variants. Results are filtered to defined genes on the panel. Reportable variants include both sequence variants and NGS-based detection of copy number variants (CNVs).  PGnome® platform: PCR-free Next Generation Sequencing (NGS) is used to sequence the coding regions of nearly all genes as well as intronic and intergenic regions. Detailed variant analysis and interpretation is focused on the coding exons and ± 10 bp into introns. Genomic variants outside of these coding regions are not investigated unless warranted (for example, if a gene of interest is highlighted by the provider, or if a single-hit pathogenic variant is found in a recessive gene). Results are filtered to defined genes on the panel. Reportable variants include sequence variants; NGS-based detection of structural variants (SV), including copy number variants (CNVs) and inversions; and repeat expansion variants in currently available relevant genes.  Variants not meeting our quality threshold through NGS alone are confirmed with an orthogonal method, including but not limited to Sanger and array.  All variants within the analyzed genes which are classified as pathogenic, likely pathogenic, risk, or variant of uncertain significance will be reported.