CHICAGO A specific pattern of X and Y chromosome lossesand in particular the loss of an important tumor-suppression genewas shown in a recent study to be associated with melanoma progression.
This "very new and very unexpected finding" could help explain gender differences that are seen in melanoma, such as the increased risk of death in men with melanoma, compared with women with melanoma, Dr. Alan Spatz said at the American Society of Clinical Oncology annual meeting, where he presented the findings.
Frozen sections from 48 melanomastaken from 32 women and 16 men with a median follow-up of 4 yearswere analyzed as part of a European Organisation for Research and Treatment of Cancer (EORTC) study. Analyses of DNA and mRNA were conducted; the end point was distant metastasis-free survival.
A significant correlation was found between DNA copy number and mRNA level for 1,455 genes (P less than .05). In the women's samples, losses in the X chromosome were significantly associated with distant metastasis-free survival (P = .009), and the affected X chromosome was always the inactive X.
In the men, losses in the Y chromosome were significantly associated with distant metastasis-free survival (P = .015), reported Dr. Spatz of Institut Gustave Roussy in Villejuif, France.
Further investigation to identify any particular gene or genes that fulfilled the criteria of being located on the X chromosome in women and escaping inactivation of X chromosome, as well as being located on the Y chromosome in men, showed that only the PPP2R3B gene, also know as PR48, did so.
The normalized expression of the gene, which is located on Xp22 in women and on Yp11 in men was found to be associated with distant metastasis-free survival at a "totally unexpected level of significance," (P = .0007), after adjusting for clinical and pathologic prognostic variables, including gender, age, ulceration, and thickness, Dr. Spatz said.
PR48 is a lesser-known subunit of a well-known and very important gene (serine/threonine protein phosphatase 2A) which he described as "kind of a gatekeeper in cell biology," he said.
PR48 mediates the dephosphorylation of CDC6 by phosphatase 2A and controls initiation of DNA replication in human cancer cells, especially melanoma, he explained.
The findings, along with those from other ongoing studies that are designed to help improve understanding of PPP2R3B biology, could potentially provide biologic clues regarding gender differences in melanoma progression and survival; the gender effect in melanoma is strongmen have been shown to have a relative excess risk of death of 1.87, compared with women with melanoma.
"We can conclude that there is a very specific pattern of X and Y chromosome losses associated with melanoma progression … and that PPP2R3B appears from this study to be a very important tumor suppression gene whose loss is associated with tumor progression.
"Does this explain the gender effect? Maybe if indeed we show that there is a differential frequency of inactivated X chromosome in females, as compared with Y chromosomebut this is still an open question," Dr. Spatz said.
In a discussion of the findings, Elizabeth Grimm, Ph.D., a professor at the University of Texas M.D. Anderson Cancer Center, Houston, called these and other emerging data a "snapshot of finest biomarker work in melanoma at this time." Dr. Spatz's work is particularly provocative, she said.
She asked, however, howgiven the findingsone would explain that the incidence of melanoma in young women is higher than that in young men. The increased incidence in men only begins to become evident around age 50 years, she noted, questioning whether other lifestyle parameters are in play.
"Just food for thought," she said.
Dr. Grimm also noted that it would be interesting, should the findings be validated in the ongoing studies that Dr. Spatz mentioned, to see how they might change the course of treatment or provide prognostic information, and to determine whether some form of gene therapy to redeliver the X and Y chromosome losses could be developed.