Sex Chromosome Tumor Suppressor Gene Might Explain Men’s Poorer Melanoma Prognosis

Canadian researchers might have discovered why melanoma is more aggressive in men than women: decreased expression of a melanoma tumor suppressor gene on the sex chromosomes.

These findings were published in the December issue of Science Translational Medicine.

“We believe that the genetic specificity of the X chromosome plays a significant function in the gender difference we observe in melanoma,” said Alan Spatz, MD, Director of Surgical and Molecular Pathology at Jewish General Hospital and head of the “X chromosome and cancer” Lab at the Lady Davis Institute in Montreal, Quebec, Canada. “And we see unique regulation of tumor suppressor genes and oncogenes in the X chromosome.”

Men are twice as likely as women to die from melanoma. Because men have only one X and a Y chromosome, whereas women have two interacting X chromosomes, Dr. Spatz and his colleagues have reasoned that X-linked tumor suppressor gene loss in men might importantly influence tumor cell behavior.

The PPP2R3B gene is found on females’ X chromosomes, but only the Y chromosome in men. It encodes a protein called PR70.

Studying mRNA levels in 49 primary melanoma biopsies and immunohistochemical assessments of PR70 levels in 339 patients’ primary melanomas, the research team found that PPP2R3B expression is higher in women than men, and is independently associated with distant metastasis-free survival (DMFS) in an apparently dose-dependent fashion, they reported.

PR70 interferes with cell replication to slow melanoma growth by disrupting DNA replication and cell cycle progression, and PR70 levels were associated with improved overall survival, the researchers found. Patients with tumors that expressed high levels of PR70 experienced a median overall survival 2.4-fold higher than patients whose melanomas did not express PR70.

“Five-year overall survival for PR70 high tumors was 65% versus 32% for PR70 low tumors,” (P < .001), they reported.

PR70 functions as an X-linked tumor suppressor gene, they concluded.

The discovery offers a “new avenue for exploring X-linked tumor suppressor genes and oncogenes” and developing new anticancer treatments, Dr. Spatz said.