It’s well established that defects in the cellular machinery that controls cell division can lead to cancer.  Now, new research shows that the risk for both brain and skin cancer can also be impacted by common DNA variations near a set of growth-regulating genes.

Five reports, published online this week in the journal Nature Genetics, show that variants near the CDKN2A and CDKN2B genes increase the risk of certain types of tumors.  Previous research has implicated these “tumor suppressor” genes in both skin and brain cancer. Mutations in CDKN2A are found in about 2% of all people with melanoma, and outright deletion of CDKN2A and CDKN2B is seen in approximately half of all brain tumors.

Two of the reports (Wrensch et al. and Shete et al.) focused on gliomas, which account for approximately 80% of all primary brain cancers and generally have a dismal prognosis.

The remaining three papers were skin cancer studies.  Two of these (Bishop et al. and Falchi et al.) focused on melanoma, while the third (Stacey et al.) looked at basal cell carcinoma.  Melanoma accounts for less than 5% of all skin cancers, but is responsible for most skin cancer deaths. Basal cell carcinoma is also serious, though not usually deadly, and is the most common type of cancer overall in people with European ancestry.

(In addition to SNPs near the CDKN2A and CDKN2B genes, several other SNPs were identified for each type of cancer.  23andMe customers can use the links in the table at the end of this post to see their data for all of these SNPs using the Browse Raw Data feature.  SNPs near the CDKN2A/CDKN2B genes are in bold.)

The disease-associated variants near the CDKN2A and CDKN2B genes were distinct for the three types of cancer studied.  This could mean that they each have separate risk-increasing effects, or that they are all pointing researchers in the direction of a single variant in the region that is involved in glioma, melanoma and basal cell carcinoma.

It’s no surprise that these genes, which play important roles in some of the most basic cellular processes, appear to be involved in several types of cancer. In fact, variation in and around CDKN2A and CDKN2B might be important for other diseases as well.  Previous research has also implicated SNPs near these genes in coronary artery disease and type 2 diabetes.

As more research is done, we can probably expect to see more variants in this region of DNA associated with more diseases.  It will be fascinating to see how they all connect to each other, and more importantly, what new insight they give scientists into how tiny DNA changes can have big health consequences.

ShareThis

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.

ShareThis

BRCA1 and BRCA2 (BRCA1/2) mutations account for most (though not all) cases of inherited breast cancer in women. These mutations are also associated with an increased risk for ovarian cancer. In men, BRCA1/2 mutations increase the risk for breast cancer and may also increase prostate cancer risk.  Research has indicated there may also be an increased risk of melanoma and pancreatic cancer in people with BRCA1/2 mutations.

Although BRCA1/2 mutations significantly increase the risk of cancer, having one of these mutations doesn’t mean a person actually has cancer or will necessarily ever get the disease.   But new research from scientists at the National Cancer Institute and the National Human Genome Research Institute, published online this week in the journal PLoS ONE, suggests that those BRCA1/2 carriers who do escape cancer may still be at risk of a shorter than average lifespan.

In a study of almost 5,300 people with Ashkenazi Jewish ancestry researchers found that, on average, both men and women who carry BRCA1/2 mutations die younger — even when cancer deaths are excluded from the analysis.  Among women free of melanoma, breast, ovarian and pancreatic cancer, BRCA1/2 mutation carriers died 5.8 years earlier (age 75.0 vs. 80.5) than those women without the mutations. In men, after excluding cases of melanoma, prostate and pancreatic cancer, BRCA1/2 mutation carriers died about 3.7 years earlier than those without the mutations (71.0 years old vs. 74.7).

“Theoretically, these mutations may either be associated with a small increase in risk of a variety of different diseases, or they may be associated with moderate increase in risk of a few major diseases,” the authors write.  They note that the current study is unable to make this distinction because it did not collect information on non-cancer related causes of death.

The researchers analyzed the effects of only the three BRCA mutations that are most common in Ashkenazi Jewish people: 185delAG in BRCA1, 5382insC in BRCA1, and 6174delT in BRCA2.  The mutations account for 80-90% of hereditary breast and ovarian cancer in this ethnic group.  But there are hundreds of other BRCA1/2 mutations that have been associated with cancer, and the authors caution that further studies taking these other BRCA1/2 mutations into account and using study subjects from diverse groups will be needed to confirm their results.

(23andMe provides data for the three BRCA1/2 mutations most commonly found in people with Ashkenazi Jewish ancestry in the BRCA Cancer Mutations (Selected) Carrier Status Clinical Report.)

The authors conclude that understanding the effects of BRCA1/2 mutations on non-cancer related deaths could eventually help scientists understand how the mutations affect cancer risk and may even facilitate efforts aimed at finding new ways of preventing disease in BRCA1/2 mutation carriers.

ShareThis