Adrenocortical Carcinoma (ACC)

Overview

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex. It may be functional (hormone-secreting: cortisol, androgens, aldosterone) or non-functional. Pediatric ACC is enriched for germline TP53 mutations (Li-Fraumeni syndrome). Adult ACC frequently harbors mutations in CTNNB1, TP53, PRKAR1A, and ZNRF3, and amplification of IGF2. Prognosis is poor for advanced disease; mitotane is the standard systemic therapy, often combined with EDP (etoposide-doxorubicin-cisplatin) chemotherapy.

Cohorts in the corpus

  • mixed_pipseq_2017 — PIPseq pediatric pan-cancer cohort (Columbia University Medical Center), which includes an adrenocortical carcinoma case among 101 high-risk pediatric patients PMID:28007021.

Recurrent alterations

  • PIPseq cohort: ALK Q1146K activating mutation identified in an adrenocortical carcinoma patient — an ALK-inhibitor target; the patient received matched targeted therapy (ALK inhibitor) PMID:28007021.
  • Pan-cancer RNA-seq fusion profiling (9,624 TCGA samples) included ACC as one of 33 cancer types; ACC samples had a median of 1 fusion/sample consistent with the pan-cancer median PMID:29617662

Subtypes

  • Pediatric ACC: strongly enriched for germline TP53 mutations (Li-Fraumeni syndrome), particularly in the Southern Brazil cluster (TP53 R337H founder mutation).
  • Adult ACC: Wnt-pathway driven (CTNNB3 mutations, ZNRF3 deletion); IGF2-overexpressing (11p15 LOH).

Therapeutic landscape

  • Mitotane (adrenostatic) monotherapy or combined with EDP chemotherapy for advanced disease.
  • IGF1R inhibitors evaluated (given frequent IGF2 overexpression) without established efficacy.
  • ALK inhibitors (crizotinib, alectinib) for ALK-mutant ACC (rare; identified in PIPseq cohort) PMID:28007021.

Sources

  • PMID:28007021 — Oberg et al. PIPseq pediatric pan-cancer sequencing program (n=101).

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