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 SNP rs2279744 were diagnosed with the disease 13 years earlier than those with GT or TT at this SNP.  In men, there was no effect of rs2279744 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.

(23andMe customers can check their data for rs2279744 using the Browse Raw Data feature.)

SNP rs2279744 is in a gene called MDM2.  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 rs2279744 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 rs2279744 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 rs2279744 shown to lead to earlier melanoma onset in the current study) have been associated with improved survival for melanoma.

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Basal cell carcinoma is not only the most common form of skin cancer in the United States – it’s the most common cancer overall. Close to a million new cases are diagnosed each year. Luckily, this type of cancer is easily treated and unlikely to spread. It can, however, cause extensive damage to surrounding tissue and bone if it’s not removed.

The biggest risk factor for basal cell carcinoma (BCC), as well as several other types of skin cancer, is sun exposure. People with light skin, hair, and eyes – who have low levels of the protective skin pigment melanin – are at especially increased risk. It’s therefore not surprising that many of the genetic variants associated with skin cancer are also linked to fair pigmentation.

A new study, published online Sunday in Nature Genetics, has identified two SNPs on chromosome 1 that increase the risk of BCC, but are not linked to a person’s coloring.

After studying more than 2,000 people with BCC and close to 36,000 controls from Iceland and Eastern Europe, Stacey et al found that each A at rs7538876 and each G at rs801114 increased the odds of developing BCC 1.28 times over those with two Gs or two Ts, respectively.
(23andMe customers can check their data by clicking on the links above that lead to our Browse Raw Data feature)

The authors of the study estimate that about 1.6% of people with European ancestry have two copies of the riskier versions at both of these SNPs, and that these people have 2.98 times the odds of BCC compared to people who have no risky copies.

The researchers then looked at the DNA of people with two other types of skin cancer that, like BCC, are related to sun. But in about 400 people with squamous cell carcinoma and about 2,000 with cutaneous melanoma, they saw no association with the SNPs.

“One unifying theme may be that genes associated with fair pigmentation confer cross-risk of all three skin cancer types because of their roles in protection from the shared risk factor of UV light, whereas the more specifically associated variants may act through different pathways,” the authors write in their report.

To investigate this idea further, the researchers looked to see if the two new BCC-associated SNPs were related to pigmentation at all. In a sample of about 5,000 Icelandic people they found that neither SNP was linked to eye or hair color, nor were either of them linked to a propensity to freckle or sun sensitivity.

“Taken together, these data suggest that the [SNPs] act through pathways other than those related to UV-susceptible pigmentation traits,” the authors write.

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