Ilir Agalliu1, Marta San Luciano2, Anat Mirelman3, Nir Giladi4, Bjorg Waro5, Jan Aasly5, Rivka Inzelberg6, Sharon Hassin-Baer7, Eitan Friedman7, Javier Ruiz-Martinez8, Jose Felix Marti-Masso8, Avi Orr-Urtreger9, Susan Bressman10, Rachel Saunders-Pullman10. 1. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York. 2. Department of Neurology, School of Medicine, University of California, San Francisco. 3. Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel. 4. Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel4Department of Neurology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. 5. Department of Neurology, St Olav's Hospital, Trondheim, Norway6Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 6. Department of Neurology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel7Parkinson's Disease and Movement Disorders Clinic, Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. 7. Parkinson's Disease and Movement Disorders Clinic, Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel8Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 8. Biodonostia Research Institute, Neurosciences Area, University of the Basque Country, San Sebastian, Spain10Neurology Department, University Hospital Donostia, San Sebastian, Spain11Center for Biomedical Research in Neurodegenerative Diseases Network, San. 9. Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel12Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 10. Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York15Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.
Abstract
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.
IMPORTANCE: Patients with Parkinson disease (PD) who harbor LRRK2G2019S 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 LRRK2G2019S 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 LRRK2G2019S 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 LRRK2G2019S 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 LRRK2G2019S 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 LRRK2G2019S 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.
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