Mar 30, 2009 - Research

Genetic Variation May Explain Why Young Women Are At Greater Risk For Melanoma Compared to Young Men

Melanoma, a rare but potentially deadly form of skin cancer, is more common in women under 40 than in men in the same age group.   After age 45, the tables are turned: men are more likely to be diagnosed with melanoma.

Between the ages of 40 and 50 happens to be when many women enter menopause or perimenopause, a time of declining estrogen levels.   This has prompted some researchers to suggest that estrogen exposure may play a part in melanoma risk.

In a report published last week in Clinical Cancer Research, researchers show that a genetic variation previously associated with several other cancers may be the link between estrogen and melanoma in younger women.   The riskier version of the variation increases the odds a woman will be diagnosed with melanoma before age 40 more than fourfold.

“Potentially, we have a genetic test that might identify pre-menopausal women who are at higher risk for melanoma.   And if that’s the case, then we might want to have increased surveillance of those patients including more frequent visits to the doctor, more rigorous teaching of skin self-examination, and other preventive steps,” said Dr. David Polsky, the study’s lead author, in a statement.

In a sample of 227 people with melanoma — 93 women and 134 men — researchers found that women with two Gs at a specific SNP in the MDM2 gene were diagnosed with the disease 13 years earlier than those with GT or TT at this SNP.   In men, there was no effect of on age at diagnosis.

About 52% of women with GG at this SNP were diagnosed with melanoma before age 50 — and 38% between ages 30 and 39.   Only about 22% of women with GT or TT were diagnosed before age 50. Although those figures are dramatic, it is important to remember that the SNP was not shown to affect melanoma risk generally, but the age at which people who do develop it are diagnosed.

Laboratory experiments have shown that the G version of this SNP causes the MDM2 gene to be turned on at higher levels in response to estrogen than the T version.

Higher levels of MDM2 protein may be relevant to melanoma, as well as other cancers, because its role in cells is to regulate a tumor suppressor protein called p53.   More MDM2 means less p53, which in turn can reduce a cell’s protection against turning into a cancer cell.

More research will be needed to confirm that there is an interaction between estrogen and the G version of SNP that affects melanoma risk.   The authors caution that their study was small, lacked information about the menopausal status of the women they studied and did not include a group of people without melanoma for comparison.

More work will also be needed to understand how the MDM2 gene and the protein it encodes affect cancer risk in general.   The G version of SNP has been associated with earlier onset for some cancers, including soft tissue sarcoma, diffuse large B-cell lymphoma, colorectal cancer, ovarian cancer and non-small cell lung cancer in women, and decreased survival in people with stomach and kidney cancer.   But there is evidence for improved survival in women with ovarian cancer who have the G version of this SNP.   Paradoxically, higher levels of the MDM2 protein (as would be expected with the G version of SNP shown to lead to earlier melanoma onset in the current study) have been associated with improved survival for melanoma.

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