Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis.
OBJECTIVE
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.


OBJECTIVE
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.


METHODS
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.


METHODS
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
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.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
Ilir
I
Agalliu
Department of Neurology, School of Medicine, University of California, San Francisco.
Marta
M
San Luciano
Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
Anat
A
Mirelman
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.
Nir
N
Giladi
Department of Neurology, St Olav's Hospital, Trondheim, Norway6Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
Bjorg
B
Waro
Department of Neurology, St Olav's Hospital, Trondheim, Norway6Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
Jan
J
Aasly
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.
Rivka
R
Inzelberg
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.
Sharon
S
Hassin-Baer
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.
Eitan
E
Friedman
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.
Javier
J
Ruiz-Martinez
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.
Jose Felix
JF
Marti-Masso
Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel12Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Avi
A
Orr-Urtreger
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.
Susan
S
Bressman
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.
Rachel
R
Saunders-Pullman
D000368:Aged; D000369:Aged, 80 and over; D005060:Europe; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D007557:Israel; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000145:classification / Q000150:complications / Q000235:genetics*; D016017:Odds Ratio; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012680:Sensitivity and Specificity; D012737:Sex Factors; D014481:United States
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine