Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson DiseaseA Pooled Analysis

http://archneur.jamanetwork.com/article.aspx?articleid=1934716

JAMA Neurology

Ilir Agalliu, MD, ScD¹; Marta San Luciano, MD²; Anat Mirelman, MD³; Nir Giladi, MD^3,4; Bjorg Waro, MD^5,6; Jan Aasly, MD, PhD^5,6; Rivka Inzelberg, MD^4,7; Sharon Hassin-Baer, MD^7,8; Eitan Friedman, MD^7,8; Javier Ruiz-Martinez, MD^9,10,11; Jose Felix Marti-Masso, MD^9,10,11; Avi Orr-Urtreger, MD^8,12; Susan Bressman, MD^13,14,15; Rachel Saunders-Pullman, MD^13,14,15

Importance  Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies.

Objectives  To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies.

Design, Setting, and Participants  Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect.

Main Outcomes and Measures  All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer.

Results  The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers.

Conclusions and Relevance  This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.