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Sex-Based Variations in Androgen Signaling Pathways in Patients With Liver Cancer

By: Joshua D. Madera, MS
Posted: Monday, March 20, 2023

Androgen signaling may play a critical role in the cellular response during genotoxic stress in hepatitis B virus (HBV)-associated hepatocellular carcinoma, which may be the result of sex-based variations in aflatoxin metabolism–related genes, according to a study published in Cellular and Molecular Gastroenterology and Hepatology. Through the repression of the DNA damage repair mechanism, tumor masses may be more easily infiltrated by T cells. Moreover, androgen signaling may improve the efficacy of anti–PD-1 immunotherapy for this type of liver cancer, explained Chunfeng Qu, MD, of the National Clinical Research Center for Cancer, Beijing, and colleagues.

A total of 101 liver tissue samples from patients with hepatocellular carcinoma caused by aflatoxin exposure and HBV infection were collected for further analysis. All patients had undergone prior hepatectomy without any radiation or systemic therapy. Patients were matched to other patients with HBV-related hepatocellular carcinoma recruited from The Cancer Genome Atlas. Tissue samples were subjected to whole-genome (n = 88), whole-exome (n = 13), and RNA sequencing (n = 87).

The study findings showed significant sex differences in aflatoxin metabolism–related genes. Males had elevated levels of AHR and CYP1A1 and reduced levels of nonhomologous DNA end joining factors including XRCC4, LIG4, and MRE11, compared with females. In addition, males demonstrated repressed tumor signaling and increased type I interferon signaling compared with females. Moreover, the addition of testosterone to cell cultures resulted in elevated levels of aflatoxin metabolism–related genes and decreased nonhomologous DNA end joining factors. Subsequently, these changes led to increased DNA leakage into the cytosol and activation of cGAS-STING.

Disclosure: The study authors reported no conflicts of interest.

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