Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy that develops in the outer layer of the adrenal glands, known as the cortex. These small glands, located above the kidneys, produce essential steroid hormones like cortisol and aldosterone. ACC is an uncommon cancer, with an annual incidence of approximately one to two cases per million people. The disease’s causes are complex, involving random changes within adrenal cells and inherited genetic predispositions. Understanding these factors is important for assessing risk and developing targeted treatments.
Sporadic Genetic Changes
The majority of Adrenocortical Carcinoma cases in adults are sporadic, arising from genetic mutations acquired during a person’s lifetime rather than being inherited. These acquired changes accumulate randomly in the DNA of adrenal cortex cells, causing them to grow and divide uncontrollably. The molecular pathways most frequently disrupted involve genes that regulate cell growth and the cell cycle.
One common alteration affects the TP53 gene, a tumor suppressor mutated in about 21% of sporadic ACC tumors. This gene normally detects DNA damage and halts cell division for repair or triggers cell death. When TP53 is mutated, this protective mechanism is lost, enabling damaged cells to proliferate.
A second major pathway is the WNT/beta-catenin signaling route, frequently altered through mutations in the CTNNB1 gene in approximately 16% of cases. The beta-catenin protein, encoded by CTNNB1, acts as a transcription factor that, when stabilized by mutation, inappropriately signals the cell to grow and divide. This uncontrolled WNT signaling drives tumor formation in the adrenal cortex.
Other sporadic changes include alterations in the CDKN2A gene, another tumor suppressor, and mutations in the promoter region of the TERT gene. TERT encodes a component of the telomerase enzyme; its activation allows cancer cells to maintain the ends of their chromosomes, granting them unlimited replication potential. The disruption of these critical cell cycle and growth signaling pathways provides the molecular foundation for most adult ACC development.
Inherited Syndromic Causes
While most adult ACCs are sporadic, a significant proportion, particularly in children, is linked to germline mutations—genetic changes present in every cell from birth. These inherited alterations are part of broader cancer predisposition syndromes that increase the risk of tumors in multiple organs, including the adrenal gland. The germline mutation provides the initial step toward cancer development, making the individual highly susceptible.
One well-established inherited risk is Li-Fraumeni Syndrome (LFS), caused by an inherited mutation in the TP53 gene. In children with ACC, the prevalence of a germline TP53 mutation can be as high as 50% to 80%, demonstrating a strong link. Individuals with LFS face an elevated lifetime risk for several cancers, and ACC is a hallmark tumor, especially at a young age.
Beckwith-Wiedemann Syndrome (BWS) is another genetic condition associated with an increased risk of childhood ACC, though the absolute risk remains low. BWS involves genetic or epigenetic alterations at the 11p15 chromosomal region, leading to overgrowth and a higher incidence of embryonal tumors. The adrenal gland is vulnerable to cancer development in this syndrome.
In adults, inherited syndromes like Multiple Endocrine Neoplasia Type 1 (MEN1) are sometimes implicated in adrenal tumor development. MEN1 results from mutations in the MEN1 gene and primarily causes tumors in the pituitary, parathyroid, and pancreas. While MEN1-related adrenal tumors are typically benign, they indicate a genetic susceptibility within the endocrine system.
Non-Genetic Risk Factors
Beyond genetic causes, epidemiological studies identify demographic and lifestyle factors that correlate with the incidence of Adrenocortical Carcinoma. These factors are not direct causal mutations but represent general risk associations in the population. The rarity of ACC makes isolating definitive environmental or non-genetic lifestyle causes challenging.
The incidence of ACC follows a bimodal age distribution, peaking during two distinct periods of life. The first peak occurs in early childhood, typically in children younger than five years old, often linked to inherited genetic syndromes. The second, larger peak affects adults between 40 and 60 years of age, where sporadic mutations are the dominant cause.
There is a consistent observation of a female predominance in ACC cases, with women accounting for about 55% to 60% of diagnoses. This higher incidence is seen across various age groups. Some studies suggest possible links to hormonal factors, such as increased risk in women who used oral contraceptives, especially before age 25.
Geographic location also plays a role in ACC risk, highlighted by a significantly higher incidence rate in specific regions, most notably Southern Brazil. This regional clustering is attributed to a specific founder mutation in the TP53 gene widespread in that population. Other potential associations, such as heavy smoking in men, have been explored but do not carry the same weight as established genetic and demographic factors.