Cisplatin, a cancer chemotherapy drug first approved by the FDA in 1978, revolutionized the treatment of many types of cancer.  Despite its effectiveness, in many cases doctors are forced to reduce the drug’s dose, or abandon it altogether, due to serious side effects on patients’ hearing.

Between 10-25% of adults and up to 60% of children being treated with cisplatin suffer from severe, permanent hearing loss in both ears. This is particularly damaging in kids, because even mild hearing loss can negatively impact learning and social development.

Researchers have suggested that genetic variants that affect the metabolism of cisplatin might explain why some people are susceptible to drug-induced hearing loss, while other patients receiving similar doses are not.  A new report, published online this week in the journal Nature Genetics, has identified variants in two genes that appear to greatly increase the risk of cisplatin-induced hearing loss.  Although the study is a small one, if replicated these findings could one day help doctors make better decisions about how to prescribe cipslatin.

A team led by Colin Ross from the University of British Columbia analyzed the DNA of 162 children (mostly of European ancestry) treated with cisplatin, focusing their search for genetic variants associated with drug-induced hearing loss on 220 genes known to be involved in the absorption, distribution, metabolism and elimination of medications and their breakdown products.

The variants with the largest effects were found in the TPMT gene.  For example, having one or two Cs at rs1142345 increased the odds of cisplatin-induced hearing loss by 10.51 times, although this result was not statistically significant once the researchers adjusted their data to account for the number of SNPs investigated.

(A larger and statistically significant effect was seen with closely related TPMT SNP, rs12201199, that 23andMe does not currently provide data for.  23andMe customers can use the links in this post to check their data using the Browse Raw Data feature.)

Rs1142345, as well as other variants that reduce the function of the TPMT enzyme, have been associated with adverse reactions to a class of drugs called thiopurines that are used as chemotherapy agents and immune system suppressants.

A second SNP associated with cisplatin-induced hearing was rs9332377 in the COMT gene.  Having one or two Ts at this SNP increased the odds of hearing loss by 5.52 times.  This result was also not statistically significant after adjusting the data.

Other variations in the COMT gene have been associated with a variety of traits, including pain sensitivity, willingness to explore new options, recovery from heart surgery, anxiety, and decreased breast cancer risk in tea drinkers.

None of the SNPs identified in this study were associated with hearing loss in children not treated with cisplatin, suggesting that their effect is specific for drug-induced hearing loss.

“These findings suggest that it may be possible identify individuals at higher risk of cisplatin otoxicity [hearing loss] based on genotype, which would improve counseling and treatment options,” the authors write.

They suggest, for example, that children with the riskier versions of the variants identified in this study could be given lower doses of cisplatin or treated instead with carboplatin, a drug that shows nearly similar cancer cure rates as cisplatin, but has less tendency to cause hearing damage.

The authors acknowledge, however, that their results will need to be replicated in independent populations before any decisions about how to use information about these variants in clinical settings can be made.  Research is also needed to understand what, if any, role these variants play in cisplatin-induced hearing loss in adult cancer patients.

Note: Recent studies by other researchers showed that variations in the megalin gene, the GSTP1 gene and the GSTM1 gene were also associated with the risk of cisplatin-induced hearing loss.  The current report from Ross et al. failed to replicate these associations.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

ShareThis

“But we always go there!”

And so begins another Friday night.  When it comes to choosing where to go to dinner, my husband likes to stick with the tried and true. I like trying out new places.

A new study suggests that the roots of this conflict could spring partly from our genes. It suggests that a DNA variation affecting the neurotransmitter dopamine influence a person’s willingness to explore new options instead of sticking with the status quo.

The finding comes from a study by Michael Frank and colleagues from Brown University and the University of Arizona. The researchers focused on how people learn from positive and negative feedback. Subjects were confronted with a clock face that counted down five seconds.  Before time was up they had to push a button to receive points.  In some trials, the experiment was set up so that the faster they pushed the button, the more points they got. In other trials, waiting longer got more points.

To the researchers’ surprise, people showed wide swings in response speed within each type of trial as they adjusted their timing in an attempt to maximize their scores. Computer models showed that a likely reason for these swings is that people change their strategy (pressing the button faster or slower) in proportion to how uncertain they are that a new strategy (speeding up or slowing down from what they’ve been doing) will yield better results.

It makes sense: If you think a new restaurant might be only marginally better than the one you usually go to (and could be worse), you’re probably not that likely to vary from the usual routine. Why risk it?

But if you really have no idea how good a place might be – who knows, it could blow your mind — you’d probably be more inclined to give it a whirl.

Further analysis of the data, which will appear in the August issue of Nature Neuroscience, showed that the extent to which a person tried out new strategies correlated with variations in the COMT gene. People who carried the “Met” version of the gene were more exploratory in the face of uncertainty about what strategy to try next than people with two copies of the “Val” version (“Met” and “Val” refer to particular amino acids encoded by different versions of the gene).

People with two copies of the Met version were the most adventurous, but even those with only one copy were statistically different in their exploration of new strategies from the people with two copies of the Val version.

(The different versions of the COMT gene are determined by rs4680, which is available to 23andMe customers in the Browse Raw Data feature.  A=Met, G =Val)

The protein encoded by the COMT gene is involved in dopamine signaling in the prefrontal cortex, an area of the brain involved in planning and decision-making.  The Met version of the gene leads to increased dopamine activity in this region and has been linked to more efficient information processing.

So does this explain my date-night drama?  Well, there’s undoubtedly more to it than genes alone, but I do have one copy of the more exploratory Met version of the COMT gene.  And my husband?  Two copies of the stuck-in-a-rut Val version.

Dopamine and Learning
In a region of the brain called the basal ganglia, dopamine helps us internalize positive and negative feedback in order to develop those “gut” feelings of what strategy will work and what won’t.

The effects of dopamine in the basal ganglia have been shown in experiments that use drugs to raise or lower levels of the neurotransmitter in the brain.  Higher dopamine levels help people learn to repeat rewarding behaviors, while lower dopamine leads to better learning from bad experiences.  In a game where “A” usually yields more points than “B,” people with boosted dopamine levels learn to choose A.  People with decreased dopamine levels learn to avoid B.

In non-medicated test subjects, genetic variations that influence dopamine signaling in the basal ganglia also impact so-called “Go” (choose A) and “NoGo” learning (avoid B). People with two copies of the A version of a variant in the DARPP-32 gene, which increases dopamine signaling, tend to be better at Go learning than their G-version-carrying friends.  Those with two copies of A at rs6277 in the DRD2 gene, which decreases dopamine signaling, tend to be better NoGo learners than people with one or two copies of the G version of this SNP.

The clock-and-button experiments Frank et al. conducted further tested the association of these two variants with Go and NoGo learning.  Trials that rewarded faster responses measured Go learning.  Trials that rewarded holding off on the action of button pushing measured NoGo learning. As expected, people with two As at the DARPP-32 variant tended to be better at Go learning than people with one or two Gs, and people with two As at rs6277 in the DRD2 gene were better at NoGo learning than people with AG or GG at this SNP.

(23andMe customers can see their data for rs6277 in the DRD2 gene using the Browse Raw Data feature.  Data for the DARPP-32 variant is not available at this time.)

Parkinson’s Disease Connection
Understanding the role of dopamine in learning from experience may have important implications for treating people with Parkinson’s disease, which is characterized by a loss of dopamine producing neurons in the brain.  Studies have shown that people with Parkinson’s have trouble with Go learning.  It’s thought that the lack of dopamine in their brains prevents the dopamine spikes needed to learn from positive feedback.

This fits with evidence that drugs that increase dopamine help people with Parkinson’s improve their performance on tasks that require Go learning.  But there is a downside:  because they flood the brain with dopamine, the normal dips in signaling that are needed to learn from negative feedback are blocked by these drugs.  This might explain why some people with Parkinson’s disease who take dopamine-increasing medications develop gambling problems – they’re overly attuned to winning, but incapable of learning from their losses.

ShareThis

A common genetic variation may influence how well a person recovers from heart surgery, a study published online yesterday in the Journal of the American Society of Nephrology suggests.

Coronary artery bypass surgery, which involves using blood vessels from elsewhere in the body to reroute blood around clogged arteries feeding the heart, increases the risk of low blood pressure and shock.  Norepinephrine can be used to bring blood pressure back up to acceptable levels, but a variation in the gene for an enzyme critical to the metabolism of this drug, COMT, may make some people less responsive.

Researchers studied 260 people who had had bypass surgery and found that those who carried an A at both copies of rs4680 went into shock more often compared to those with other genotypes (69% vs. 57% in AG people and 46.6% in GG people). The A version of rs4680 produces a less efficient version of the COMT enzyme.

Prolonged shock, lasting more than 48 hours, was also more frequent in people with two As (25% vs. 13% for AG and 6.8% for GG). Because the body responds to shock by restricting blood flow to the kidneys, people with two As at rs4680 also had greater frequency of acute kidney injury.

The median hospital stay after bypass surgery was longer for people with two As at rs4680: nine days vs. eight days for AG and seven days for GG.

(23andMe customers can check their data for rs4680 using the Browse Raw Data feature.)

More research on the effects of the COMT variation investigated in this study and variations in other genes that could also affect recovery after bypass surgery will be needed.  But if confirmed, the researchers suggest that their findings could help tailor drug regimens and lead to better outcomes.

“If confirmed in larger trials, preoperative COMT genotyping together with known clinical risk factors could aid in preoperative risk stratification to anticipate occurrence of circulatory and renal dysfunction, and prolonged recovery.  Patients thus identified may benefit from an individualized treatment…” the authors conclude.

• Having two As at rs4680 in the COMT gene has been associated with a number of conditions, ranging from neuropsychiatric and hormonal disorders to cardiovascular diseases. 23andMe customers can read about how this SNP interacts with tea drinking to affect breast cancer risk in the Breast Cancer Risk Modifiers Research Report.  There is also a Research Report about another SNP in the COMT gene and its effects on pain sensitivity.

ShareThis