Scientists have struggled for more than 50 years to resolve the controversial claim that individuals with Down's syndrome are less likely to develop solid tumours. Although the idea has become accepted dogma in recent years, studies hoping to prove or disprove the theory have been less than definitive. Reports of research showing cancer rates in people with Down's syndrome to be equal to or greater than those in the general population appear in the literature just as frequently as those concluding that rates are lower.

The difficulty of searching for low-frequency cancers in an already small sample size (only 1 in 700 people have the extra copy — known as 'trisomy' — of chromosome 21 that leads to Down's syndrome), confounds epidemiological studies. “Looking for lower incidence of an already very rare event makes it difficult to obtain an adequate sample size, which is the Achilles' heel in these studies,” says Roger Reeves, a geneticist at the Johns Hopkins University School of Medicine in Baltimore, Maryland. In addition, he says, some studies make no adjustments for the generally shorter lifespan seen in Down's syndrome.

About five years ago, Reeves made what he calls a “leap of faith” after taking a good look at the conflicting epidemiological data. He decided that the statistics had reached an impasse and opted to take a biological approach based on mouse models of Down's syndrome. By studying mice with three copies of a group of mouse genes that correspond to a subset of genes found on human chromosome 21, Reeves and his colleagues have pin-pointed a dosage-dependent tumour 'repressor' gene that may hold promise for cancer prevention (see page 73).

Early in the study, the team showed that a genetic cross between trisomic mice and mice carrying a gene associated with a high proportion of intestinal cancers reduced tumour formation by almost half. Then, Reeves' doctoral student, Thomas Sussan, narrowed the search for the responsible genes by using a mutant mouse with fewer triplicate genes — just 33.

Having found that this also lowered tumour incidence, the team looked more closely at the subset of 33 genes. They found that, despite being known to cause cancer when mutated, in triplicate the transcription factor Ets2 decreases tumour incidence.

As he became more involved with individuals with Down's syndrome, Reeves uncovered much misinformation about their quality of life. He cites published studies indicating that 80–90% of pregnant mothers who are told they will give birth to a child with Down's syndrome are likely to terminate the pregnancy. Yet, “they have little idea of what it means to have a child with Down's syndrome or to be a person with Down's syndrome,” says Reeves. He notes that people with Down's syndrome have become actors, authors and musicians — feats many of us only aspire to. And just in the past two years, he says, several studies have made breakthroughs in developing pharmacological approaches to address cognitive deficits that will allow those with Down's syndrome to live even fuller lives.

Reeves sees a great irony in the fact that although their quality of life is often disavowed, it is the genomes of those with three copies of chromosome 21 that may ultimately yield a key to cancer prevention. “If trisomy 21 weren't compatible with a full life, it is unlikely that a study such as this would have been undertaken, let alone funded,” he says. “Who would be foolish enough to randomly overexpress genes thought to cause cancer in order to prevent it?”