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.

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Each type of cancer has its own idiosyncrasies, but when it comes down to it, they all have one thing in common: failure to control cellular growth. So it’s somewhat surprising that when genome-wide association studies have looked for single common variations associated with the risks for multiple types of cancer, they have for the most part identified only SNPs that are peculiar to just one form of the disease.

A new study published online Sunday in Nature Genetics may signal a change in this trend. A team of researchers led by Thorunn Rafnar and Patrick Sulem of deCODE Genetics in Iceland describes how a SNP they originally found to be associated with the risk for developing basal cell carcinoma (BCC), a type of skin cancer, is also linked to increased odds for four other cancers.

In a study of more than 33,800 cancer patients and 45,800 controls, the scientists found that the C version of rs401681 is associated with increased odds of lung, bladder, prostate and cervical cancer, in addition to the previously found association with BCC. This variation decreases the odds of cutaneous melanoma, another type of skin cancer.

(23andMe customers can check their data for this SNP, rs401681, using the Browse Raw Data feature. A table at the end of this post provides details about its effect on different cancers).

The C version of rs401681 was also marginally, although not significantly, associated with increased odds of endometrial cancer and decreased odds of colorectal cancer.

There was no association of the SNP with cancer of the breast, kidney, stomach, thyroid, ovary or pancreas, nor with lymphoma, multiple myeloma or squamous cell carcinoma (a third type of skin cancer). The authors say that further investigation in even larger samples will be needed to determine if there truly is no association, or if they just haven’t picked it up yet.

An association was also found between rs2736098, a nearby SNP, and four of the five cancers that were associated with rs401681. 23andMe does not currently provide data for rs2736098.

Both SNPs are near a gene involved in maintaining the protective stretches of DNA attached to the ends of chromosomes called telomeres. The authors suggest that these SNPs, or other nearby variations, may lead to shortened telomeres, which are associated with several types of cancer.

Telomere length is determined in part by genetics, but environmental factors such as smoking and radiation can also shorten them. The authors note “four of the five cancers associated with the risk variants are cancer types that have strong environmental contributions to risk – smoking and occupational exposures for lung and bladder cancer, UV irradiation for BCC and infection with human papillomavirus for cervical cancer.” More research could help explain the exact relationship between the genetic variations found in this study and the environmental causes of these cancers.

*Effect is the increase or decrease in odds compared with someone with two copies of the T version of rs401681.

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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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