Revisiting the Link Between Huntington's Disease and Cancer: Evidence from the Enroll-HD dataset.

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder (NDD) caused by CAG repeat expansion in the HTTgene. Previous studies suggested an inverse comorbidity between HD and malignancies, possibly linked to pro-apoptotic mechanisms. In this study, we aimed to investigate the prevalence of malignancies in a large HD cohort (Enroll-HD) and explore demographic, genetic, and clinical factors associated with cancer risk. METHODS: We analyzed baseline data from the Enroll-HD PDS6 dataset (N = 24,686; 18,892 HD gene expansion carriers [HDGECs], 5,794 controls). Cancer diagnoses were identified using ICD-10 codes (C00-C97). Prevalence was compared between groups using Chi-square and Mantel-Haenszel tests. Logistic regression models were used to assess associations with demographic, lifestyle, and genetic variables; models included age, sex, tobacco use, alcohol abuse, drug abuse, and CAG repeat length as covariates. Associations between cancer status and clinical outcomes were examined using general linear and linear mixed-effects models. RESULTS: Overall cancer prevalence did not differ significantly between HDGECs (4.92%) and controls (5.23%). However, pre-motor-manifest HDGECs had a significantly lower prevalence (3.62%) compared with both controls and motor-manifest patients (5.57%). Similarly, cancer prevalence increased progressively across HD Integrated Staging System (HD-ISS) stages. Logistic regression identified older age (HDGECs: OR = 1.05, 95% CI 1.05-1.06; controls: OR = 1.07, 95% CI 1.06-1.08) and female sex (HDGECs: OR = 1.22, 95% CI 1.07-1.40; controls: OR = 1.46, 95% CI 1.13-1.88) as risk factors for malignancy in both groups. In contrast, shorter CAG repeat length was associated with increased cancer prevalence only in HDGECs (OR = 0.89, 95% CI 0.86-0.92). No specific cancer type was over- or under-represented. Among HDGECs, a history of cancer was associated with better baseline motor (UHDRS TMS estimate = -5.10, SE = 0.73, p < 0.0001) and functional outcomes (UHDRS TFC estimate = 0.64, SE = 0.58, p < 0.0001), but was not associated with differences in longitudinal trajectories. In contrast, among controls, cancer history was associated with worse motor (UHDRS TMS estimate = 0.68, SE = 0.18, p < 0.0001) and functional outcomes (UHDRS TFC estimate = -0.12, SE = 0.04, p = 0.001). CONCLUSIONS: These findings do not support a strong overall protective effect of HD against malignancy. Instead, cancer prevalence was associated with disease stage, age, and CAG repeat length. The lower cancer prevalence observed in premanifest HDGECs may reflect a combination of biological factors and age-related confounding. Further mechanistic and longitudinal studies are needed to clarify the interplay between mutant huntingtin, apoptosis, and cancer biology.