# Lifetime risk of cancer in carriers of intermediate alleles in the HTT gene

## TL;DR

The study found no reduced cancer risk in carriers of intermediate HTT gene alleles, but suggests a possible protective effect for rare reduced penetrance alleles.

## Contribution

This is the first study to analyze cancer risk in HTT intermediate allele carriers and reduced penetrance alleles using a large population cohort.

## Key findings

- Intermediate HTT allele carriers (CAG 27–35) had similar cancer risk compared to normal allele carriers.
- Reduced penetrance alleles (CAG 36–39) showed a trend toward lower cancer risk but with wide confidence intervals.
- The study suggests a potential dose-dependent protective effect of longer CAG repeats against cancer.

## Abstract

Previous studies have found a markedly reduced risk of cancer among Huntington’s disease (HD) patients with CAG ≥ 40, but data on cancer risk at shorter repeat numbers are lacking. The study includes 8149 subjects from Northern Sweden Health and Disease Study. Genotyping yielded a large number of intermediate allele carriers (IA, CAGn 27–35, (n = 497), normal alleles (CAGn 17–26,n = 6584), short alleles (CAG ≤ 16, n = 169) and 31 subjects with > 35 repeats, including reduced penetrance alleles (36–39; not guaranteed to suffer HD symptoms during a normal lifespan) and HD alleles > 39. Cancer diagnoses were retrieved from the Swedish Cancer Registry and the Hospital Discharge Registry and death certificates. We used Kaplan-Meier curves and Cox proportional hazard models to estimate the time to cancer, on strata of the population created by CAG repeat number intervals. Smoking status, BMI, as well as alcohol consumption were included in the models. 2735 participants (33.6%) had ≥ 1 cancer type. The Hazard-Ratio (HR) for IA carriers compared with normal alleles was similar, 0.97 CI 0.82–1.15). The reduced penetrance allele group (CAGn 36–39, n = 29) had HR of 0.54 CI 0.22–1.30 similar to what has been reported with a full penetrance allele. Intermediate allele carriers as a group did not have a reduced risk of cancer. It remains possible that reduced penetrance alleles confer lower risk of cancer, with signs of a dose-dependent protective effect of CAG repeat length. The latter finding needs to be confirmed in even larger cohorts as these repeat numbers are relatively rare.