Abstract
Importance
Parkinson disease (PD) patients who harbor LRRK2 G2019S mutations may have increased risks of non-skin cancers. However, the results have been inconsistent across studies.
Objective
To analyze pooled data from five centers to further examine the association between LRRK2 G2019S mutation and cancer among PD patients 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 1,549 PD patients recruited across five 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, non-skin 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 PD patients. 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 non-skin 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 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 five 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 PD patients are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.
Keywords: LRRK2 gene, G2019S mutation, Parkinson Disease, cancer, non-skin cancer, hormone-related cancers, breast cancer, pooled analysis
Introduction
Parkinson disease (PD) and cancer have opposite biological mechanisms: PD is characterized by apoptosis and premature neuronal degeneration, the hallmark of cancer is uncontrolled cell proliferation1. However, a link between PD and cancer was suspected when higher incidence rates of melanoma were observed among PD patients2. The excess melanoma risk might be the result of a shared relationship between tyrosinase and melanin, but not L-dopa treatment3–6. The overexpression of alpha-synuclein leads to cell degeneration in the brain. In the skin, the overexpression may inhibit tyrosinase and tryrosine hydroxylase and thus decrease the levels of protective melanin3. In turn, the lower melanin levels could increase a person’s susceptibility to the deleterious effects of ionizing radiation and environmental toxins leading to melanoma3. Family members of PD patients are more likely to develop melanoma, and patients with melanoma and their family members have an increased PD risk7–9.
PD patients have lower risks for non-skin cancers 5,6,10,11. A meta-analysis of 29 studies reported relative risks (RRs) of 0.61 (95%CI 0.58–0.65) and 0.76 (95%CI 0.65–0.89) for smoking-related and others cancers, respectively, among PD participants10. However, the results have been inconsistent, with some studies indicating increased risks for breast cancer 5,6,12, and prostate cancer 8. A potential explanation for lower rates of non-skin cancers could be that the prevalence of smoking and other lifestyle risk factors are usually low in PD patients; although differences in genetic susceptibility could play a role 6,13.
A promising approach to disentangle the shared genetic component between cancer and PD is to hone the analysis using identified genetic forms of parkinsonism. Four PD susceptibility genes (SYN, Parkin, DJ-1 and LRRK2) could potentially link cancer and PD, since they all encode proteins with biological mechanisms that increase cell growth or decrease cell death 1,14. The LRRK2 (leucine rich repeat kinase 2) gene (OMIM, 609007, chromosomal location, 12q12) encodes multiple domains, including a kinase domain and a ras-oncogene-like guanosine triphosphatase domain, which has similar structural position as the B-RAF kinase associated with melanoma15,16. The most common LRRK2 mutation, G2019S 17,18 has been associated with increased risk of non-skin cancers 19,20 and breast cancer 19, whereas the R1441G/C mutation was associated with colon cancer 21. However results across the studies are inconsistent. Among 732 PD patients in Spain there was no association between R1441G/C or G2019S mutations and cancer outcomes 22.
Because knowledge of a possible link with cancer may guide screening and counseling practices for both LRRK2 mutation carriers with PD and asymptomatic carriers, it is important to examine associations between such mutations and cancer in a larger sample of PD patients, as well as to evaluate whether study differences may account for the discrepancy in findings. Therefore, we conducted a pooled analysis examining the relationship between LRRK2 G2019S mutation and cancer outcomes among PD patients recruited in five centers located in Europe, Israel, and the United States.
Methods
Study Participants and Data Collection
The study was approved by the Institutional Review Boards of each participating institution, and written informed consent was obtained from all patients. The participants did not receive financial compensation. PD patients (n=1,549) were recruited from five movement disorders clinics located in Israel (Sheba Medical Center and Sourasky Medical Center, Tel Aviv), Norway (St. Olav’s Hospital, Trondheim), Spain (University Hospital Donostia, San Sebastian), and the United States (Mt. Sinai Beth Israel Medical Center, New York). Detailed descriptions about study participants, data collection, LRRK2 genotyping and cancer outcomes for three of the centers have been published 19,20,22,23 and are summarized for all five centers in the eTable in the Supplement. Briefly, at all centers, PD patients were queried regarding demographic and lifestyle factors as well as, personal and family history of PD and other diseases, including self-reported cancer, type of cancer, and age at diagnosis. The confirmation of self-reported cancer outcomes varied slightly by study site. In Israel and New York cancer outcomes were confirmed by reviewing the medical records of oncologists and surgeons 19,20; whereas in Spain and Norway, cancer outcomes were confirmed with medical records and tumor registry databases 22. All PD patients included in the present analysis were genotyped for LRRK2 G2019S mutation. Genotyping of the LRRK2 R1441G/C mutation was done only in one center 22; thus, we did not include that mutation in the present analysis. Other differences across centers included matching of patients with LRRK2 PD patients and controls, the burden of data collection, and whether carriers of GBA124 or BRCA1/2 mutations were excluded (eTable in the Supplement).
Statistical Analysis
We compared characteristics of LRRK2 G2019S mutation carriers with those of non- carriers using unpaired, two-tailed t tests (for continuous, normally distributed variables), and chi-square tests (for categorical variables). The significance level was set at α=.05. Logistic regression models were used to examine the associations between G2019S mutation and several outcomes: all cancers combined, non-skin cancers (all cancers, excluding non-melanoma skin cancer and melanoma), smoking-related cancers, hormone-related cancers, and other cancers to estimate odds ratios (ORs) and 95% CIs25. Smoking-related cancers included lung and bladder cancers; there was only one patient with oropharyngeal cancer, which was not included in this group owing to potential confounding by human papillomavirus infection. Hormone-related cancers included breast and ovarian cancers in women (there were no endometrial cancers), and prostate cancer in men. In addition, we separately assessed the association of G2019S mutation and each type of cancer.
We initially examined the unadjusted association between LRRK2 G2019S mutation and cancer outcomes, and then we adjusted the analyses using different statistical models. In the first model, association between G2019S mutation and cancer outcomes were adjusted for age at the time of the first cancer diagnosis for patients with available data (n=131), or age at the last clinic visit for all other PD patients. Because of the heterogeneity across the five centers, the associations between G2019S mutation and cancer outcomes were estimated using mixed-effect, logistic models, adjusting for age as fixed effect and study center as a random effect (model 2). In model 3, the associations were adjusted for age and ethnicity (Ashkenazi Jewish [AJ] vs. non-AJ) as fixed effects and study center was modeled as a random effect. For hormone-related cancers, all analyses were carried out in sex-specific strata.
We also investigated whether associations between LRRK2 G2019S mutation and cancer varied by ethnicity (AJ vs. others). We conducted these analyses for all cancer combined, non-skin cancers, and hormone-related cancers. To test effect modification, interaction terms between G2019S mutation and ethnicity were included in models containing the main effects in separate logistic regression models. The log likelihood of models with main effects were compared with the log likelihood of models that contained main effects and the interaction terms, using a likelihood ratio test to determine statistical significance of interactions 26.
Finally, we conducted a sensitivity analysis to determine the influence of the study center on the associations between LRRK2 G2019S mutation and cancer outcomes. The associations between G2019S mutation and cancer outcomes were estimated using model 2 (adjusted for age and study center) for all five centers and then by excluding each center, one at a time, to determine the change in OR and 95% CI. All statistical analyses were performed using STATA, version 12 (StataCorp).
Results
The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all PD patients. Demographic characteristics, clinical characteristics, and cancer outcomes for 1,549 PD patients from five centers are presented in Table 1, stratified also by LRRK2 G2019S mutation status. Mutation carriers were slightly younger at PD diagnosis (57.8±11.8 vs. 62.4±11.6 years, p<0.0001) and more likely to be women (53.1%) and of AJ descent (76.8%) in comparison with non-carriers. Almost half (49.2%) of PD patients were from Spain, 38.7% were from Israel, 10.5% were from the United States and 1.6% were from Norway. There was large variability in percentages of G2019S mutation carriers by study center, owing to differences in geographic location, ethnicity, and data collection procedures (eTable in the Supplement). Information on smoking was collected only for a subset of PD patients (n=304) in two centers (Israel and United States); however, LRRK2 mutation carriers were similar to non-carriers with respect to smoking status (p=0.97).
Table 1.
Characteristics and cancer outcomes for all Parkinson disease (PD) patients, as well as stratified by LRRK2 G2019S mutation carrier status
| Characteristics | Total (N=1,549) |
LRRK2 Mutation Carriers (N=177) |
LRRK2 Mutation Non-Carriers (N=1,372) |
P-value* | |||
|---|---|---|---|---|---|---|---|
| Age at exam (y); mean SD | 70.9 | 10.8 | 69.9 | 11.1 | 71.0 | 10.8 | 0.21 |
| Age at PD diagnosis (y); mean SD | 61.9 | 11.7 | 57.8 | 11.8 | 62.4 | 11.6 | <0.0001 |
| Duration of PD (y); mean SD | 9.8 | 7.0 | 11.2 | 8.7 | 9.5 | 6.7 | 0.05 |
| Study Center; n % | <0.0001 | ||||||
| Israel (Tel Aviv, Sheba) | 459 | 29.6 | 49 | 27.7 | 410 | 29.9 | |
| Israel (Tel Aviv, Sourasky) | 140 | 9.0 | 68 | 38.4 | 72 | 5.3 | |
| Norway | 25 | 1.6 | 4 | 2.3 | 21 | 1.5 | |
| Spain (San Sebastian) | 762 | 49.2 | 25 | 14.1 | 737 | 53.7 | |
| US (Beth Israel, New York City) | 163 | 10.5 | 31 | 17.5 | 132 | 9.6 | |
| Sex; n % | 0.009 | ||||||
| Male | 869 | 56.1 | 83 | 46.9 | 786 | 57.3 | |
| Female | 680 | 43.9 | 94 | 53.1 | 586 | 42.7 | |
| Ethnicity; n % | <0.0001 | ||||||
| Ashkenazi Jews (both parents) | 589 | 38.0 | 136 | 76.8 | 453 | 33.0 | |
| Sephardic Jews (both parents) | 136 | 8.8 | 7 | 3.4 | 129 | 9.4 | |
| Other Ethnicity, Caucasian | 824 | 53.2 | 34 | 19.2 | 790 | 57.6 | |
| Smoking status ascertained; N | 304 | 100 | 204 | 0.97 | |||
| Never smoker; n % | 187 | 61.5 | 61 | 61.0 | 126 | 61.8 | |
| Former smoker; n % | 103 | 33.9 | 34 | 34.0 | 69 | 33.8 | |
| Current smoker; n % | 14 | 4.6 | 5 | 5.0 | 9 | 4.4 | |
| Cancer Outcomes | |||||||
| All Cancers Combined; n % | 250 | 16.1 | 40 | 22.6 | 210 | 15.3 | 0.013 |
| Number of Cancers Reported; n % | 0.04 | ||||||
| 1 | 223 | 14.4 | 32 | 18.1 | 191 | 13.9 | |
| 2 or 3 | 27 | 1.7 | 8 | 4.5 | 19 | 1.4 | |
| Age at diagnosis of first cancer§ (y); mean SD | 67.5 | 9.8 | 62.5 | 10.8 | 68.3 | 9.4 | 0.023 |
| Skin Cancer (any); n % | 49 | 3.2 | 10 | 5.7 | 39 | 2.8 | 0.05 |
| Melanoma; n % | 22 | 1.4 | 5 | 2.8 | 17 | 1.2 | 0.09 |
| All Non-Skin Cancers (excluding skin & melanoma) | 201 | 13.0 | 32 | 18.1 | 169 | 12.3 | 0.032 |
| Smoking-related cancers †; n % | 20 | 1.3 | 2 | 1.1 | 18 | 1.3 | 0.84 |
| Lung cancer; n % | 9 | 0.6 | 2 | 1.1 | 7 | 0.5 | 0.31 |
| Bladder cancer; n % | 11 | 0.7 | 0 | - | 11 | 0.8 | 0.23 |
| Hormone-related cancer‡; n % | 97 | 6.3 | 20 | 11.3 | 77 | 5.6 | 0.003 |
| Breast Cancer; n % | |||||||
| Breast Cancer (women) | 39 | 5.7 | 12 | 12.8 | 27 | 4.6 | 0.002 |
| Breast Cancer (men) | 2 | 0.2 | 1 | 1.2 | 1 | 0.13 | 0.05 |
| Ovarian Cancer; n % | 10 | 1.5 | 0 | - | 10 | 1.7 | 0.2 |
| Prostate Cancer; n % | 48 | 5.5 | 8 | 9.6 | 40 | 5.1 | 0.08 |
| Colon Cancer; n % | 35 | 2.3 | 6 | 3.4 | 29 | 2.1 | 0.28 |
| Kidney Cancer; N % | 10 | 0.7 | 2 | 1.1 | 8 | 0.6 | 0.39 |
| Hematologic/Lymphoma; n % | 17 | 1.1 | 1 | 0.6 | 16 | 1.2 | 0.47 |
| Meningioma; n % | 13 | 0.8 | 3 | 1.7 | 10 | 0.7 | 0.19 |
P-values from t-tests (continuous) and chi-square tests (categorical variables) comparing LRRK2 mutation carriers vs. non-carriers
Age at diagnosis of first cancer was available only for a subset of PD patients (n=131); only one PD patient reported 3 cancers
Smoking-related cancers include lung and bladder cancers. Only one patient reported a cancer of the oropharynx, which was not included due to lack of HPV-status and thus potential confounding by HPV
Hormone-related cancers include prostate cancer in men and breast and ovarian cancers in women (there were no endometrial/gynecologic cancers reported); percentages of gender-specific hormonal cancers are based on the number of men and women
A total of 250 cancer outcomes (16.1%) were reported from all PD patients; of these, 201 were non-skin cancers. The proportions of all cancers and non-skin cancers were higher among LRRK2 G2019S mutation carriers vs. non-carriers: 22.6% vs. 15.3% for all cancers (p=0.01), and 18.1% vs. 12.3%, respectively for non-skin cancer (p=0.03). In comparison with non-carriers, G2019S mutation carriers were three times more likely to report two or more cancers (4.5% vs. 1.4%; p=0.04) and younger age at the time of the first cancer diagnosis (62.5±10.8 vs. 68.3±9.4 years; p=0.02).
Table 2 provides associations of LRRK2 G2019S mutation with overall cancer and various cancer outcomes among PD patients, using three different statistical models. Although we did not observe any statistically significant association between LRRK2 G2019S mutation and all cancers combined, there was a 57% increased risk (95%CI 1.04 – 2.38) for non-skin cancers among LRRK2 G2019S mutation carriers in comparison with non-carriers in models adjusted for age and study center. The association increased slightly (OR, 1.62; 95%CI, 1.04 – 2.52) when the analysis was also adjusted for ethnicity (AJ vs. other). There was a statistically significant positive association between LRRK2 G2019S mutation and hormone-related cancers, which was driven mostly by breast cancer in women. In models adjusted for age and study center, OR was 2.06 (95%CI, 1.22–3.47) for hormone-related cancers in all patients and 2.88 (95%CI, 1.39 – 5.98) for breast cancer in women among G2019S mutation carries vs. non-carriers. The ORs for these outcomes were slightly attenuated to 1.87 (p=0.03) and 2.34 (p=0.04) respectively, when the models were also adjusted for AJ ethnicity. There was an OR of 2.21 (p=0.07) for prostate cancer among male G2019S mutation carriers. There were no associations between LRRK2 G2019S mutations and smoking-related cancers or other types of cancer.
Table 2.
Associations of LRRK2 G2019S mutation with overall cancer and various cancer types among Parkinson patients
| Cancer Outcomes | Non-Carriers (n=1,372) |
Carriers (n=177) |
Model 1* | Model 2† | Model 3‡ | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | OR* | 95% CI | p | OR† | 95% CI | p | OR‡ | 95% CI | p | |
| No | 1,162 | 89.5 | 137 | 10.5 | 1 | - | 1 | - | 1 | - | |||
| All Cancers combined | 210 | 84.0 | 40 | 16.0 | 1.49 | 0.99 – 2.24 | 0.057 | 1.49 | 0.99 – 2.24 | 0.057 | 1.37 | 0.92 – 2.04 | 0.13 |
| Skin Cancer | 39 | 79.6 | 10 | 20.4 | 2.11 | 1.03 – 4.31 | 0.04 | 1.11 | 0.51 – 2.40 | 0.80 | 1.03 | 0.48 – 2.22 | 0.93 |
| Melanoma | 17 | 77.3 | 5 | 22.7 | 2.36 | 0.86 – 6.50 | 0.10 | 1.95 | 0.67 – 5.72 | 0.22 | 1.62 | 0.56 – 4.67 | 0.37 |
| No | 1,203 | 89.2 | 145 | 10.8 | 1 | - | 1 | - | 1 | - | |||
| All Non-Skin Cancers | 169 | 84.1 | 32 | 15.9 | 1.57 | 1.04 – 2.38 | 0.034 | 1.57 | 1.04 – 2.38 | 0.034 | 1.62 | 1.04 – 2.52 | 0.031 |
| Smoking-related cancers | |||||||||||||
| No | 1,354 | 88.5 | 175 | 11.5 | 1 | - | 1 | - | 1 | ||||
| Yes | 18 | 90.0 | 2 | 10.0 | 0.84 | 0.19 – 3.64 | 0.81 | 1.04 | 0.22 – 4.94 | 0.96 | 1.20 | 0.25 – 5.76 | 0.82 |
| Lung Cancer | 7 | 77.8 | 2 | 22.2 | 2.15 | 0.44 – 10.46 | 0.34 | 2.40 | 0.43 – 13.45 | 0.32 | 2.40 | 0.42 – 13.82 | 0.33 |
| Bladder Cancer | 11 | 100 | 0 | - | - | - | - | - | - | - | - | - | - |
| Hormone-related cancers§ | |||||||||||||
| No | 1,295 | 89.2 | 157 | 10.8 | 1 | - | 1 | - | 1 | - | |||
| Yes | 77 | 79.4 | 20 | 20.6 | 2.06 | 1.22 – 3.47 | 0.007 | 2.06 | 1.22 – 3.47 | 0.007 | 1.87 | 1.07 – 3.26 | 0.03 |
| Breast Cancer, women | 27 | 69.2 | 12 | 30.8 | 2.88 | 1.39 – 5.97 | 0.004 | 2.88 | 1.39 – 5.98 | 0.004 | 2.34 | 1.05 – 5.22 | 0.04 |
| Ovarian Cancer | 10 | 100 | - | - | - | - | - | - | - | - | - | - | - |
| Prostate Cancer, men | 40 | 83.3 | 8 | 16.7 | 2.05 | 0.92 – 4.55 | 0.08 | 2.05 | 0.92 – 4.55 | 0.08 | 2.21 | 0.95 – 5.18 | 0.07 |
| Other Cancer Types | |||||||||||||
| Colon Cancer | 29 | 82.9 | 6 | 17.1 | 1.68 | 0.69 – 4.11 | 0.26 | 1.68 | 0.69 – 4.11 | 0.26 | 1.92 | 0.74 – 5.00 | 0.18 |
| Kidney/Renal Cancer | 8 | 80.0 | 2 | 20.0 | 1.93 | 0.41 – 9.17 | 0.41 | 1.93 | 0.40 – 9.17 | 0.41 | 1.93 | 0.40 – 9.17 | 0.41 |
| Hematologic/Lymphoma | 16 | 94.1 | 1 | 5.9 | 0.48 | 0.06 – 3.68 | 0.48 | 0.48 | 0.06 – 3.68 | 0.48 | 0.48 | 0.06 – 3.68 | 0.48 |
| Meningioma | 10 | 76.9 | 3 | 23.1 | 2.40 | 0.65 – 8.78 | 0.19 | 2.38 | 0.61 – 9.21 | 0.21 | 2.38 | 0.61 – 9.21 | 0.21 |
Percentages represent row percent
OR and 95% CI for model 1 were adjusted for age at cancer diagnosis (for PD patients diagnosed with cancer) and age at exam (for other PD patients)
OR and 95% CI for model 2 were estimated using mixed effect models adjusting for age at cancer diagnosis (for PD patients diagnosed with cancer) and age at exam (for other PD patients) as fixed effect, and study center as random effects
OR and 95% CI for model 3 were estimated using mixed effect models adjusting for age at cancer diagnosis (for PD patients diagnosed with cancer) and age at exam (for other PD patients) and ethnicity (Ashkenazi Jews vs. other) as fixed effect, and study center as random effect
Analyses for hormonal cancers were carried out in strata by gender. Bold font represents results that are statistically significant at p<0.05
We examined whether the associations between LRRK2 G2019S mutation and cancer outcomes were different between AJ patients vs. those of other ethnicities (Table 3). There were similar ORs for G2019S mutation and non-skin cancers between AJ (OR, 1.59) and others (OR, 1.74; p= 0.84 for interaction). For breast cancer, although there was a suggestion that the risk associated with G2019S mutation was lower among AJ women (OR, 1.77; 95%CI, 0.70 – 4.48) in comparison with women of other ethnicities (OR, 4.65; 95%CI, 1.21 – 17.93), the p-value for interaction was not statistically significant (p=0.26). Finally, for prostate cancer there were similar ORs for AJ men (OR, 2.12) and men of other ethnic groups (OR, 2.47; p=0.85 for interaction).
Table 3.
Associations of LRRK2 G2019S mutation with overall cancer and hormonal cancers, stratified by Ashkenazi Jewish ethnicity
| Ashkenazi Jewish (n=589) | |||||||
|---|---|---|---|---|---|---|---|
| Cancer Outcomes | Non-Carriers (n=453) |
Carriers (n=136) |
Model adjusted for age and study center* |
||||
| N | % | N | % | OR* | 95% CI | p | |
| No | 364 | 77.5 | 106 | 22.5 | 1 | - | |
| All Cancers combined | 89 | 74.8 | 30 | 25.2 | 1.20 | 0.74 – 1.94 | 0.46 |
| No | 399 | 78.1 | 112 | 21.9 | 1 | - | |
| All Non-Skin Cancers | 54 | 69.2 | 24 | 30.8 | 1.59 | 0.94 – 2.70 | 0.08 |
| Hormone-related cancers§ | |||||||
| No | 423 | 77.8 | 121 | 22.2 | 1 | - | |
| Yes | 30 | 66.7 | 15 | 33.3 | 1.60 | 0.80 – 3.18 | 0.18 |
| Breast Cancer, women | 12 | 57.1 | 9 | 42.9 | 1.77 | 0.70 – 4.48 | 0.23 |
| Prostate Cancer, men | 13 | 68.4 | 6 | 31.6 | 2.12 | 0.77 – 5.81 | 0.15 |
| Non-Ashkenazi Jewish (n=960) | |||||||
| Cancer Outcomes | Non-Carriers (n=919) |
Carriers (n=41) |
Model adjusted for age and study center* |
||||
| N | % | N | % | OR* | 95% CI | p | |
| No | 798 | 96.3 | 31 | 3.7 | 1 | ||
| All Cancers combined | 121 | 92.4 | 10 | 7.6 | 2.20 | 1.05 – 4.61 | 0.04 |
| No | 804 | 96.1 | 33 | 3.9 | 1 | ||
| All Non-Skin Cancers | 115 | 93.5 | 8 | 6.5 | 1.74 | 0.78 – 3.88 | 0.17 |
| Hormone-related cancers§ | |||||||
| No | 872 | 96.0 | 36 | 4.0 | 1 | - | |
| Yes | 47 | 90.4 | 5 | 9.6 | 2.67 | 0.99 – 7.15 | 0.051 |
| Breast Cancer, women | 15 | 83.3 | 3 | 16.7 | 4.65 | 1.21 – 17.93 | 0.03 |
| Prostate Cancer, men | 27 | 93.1 | 2 | 6.9 | 2.47 | 0.53 – 11.43 | 0.25 |
Percentages represent row percent
OR and 95% CI were adjusted for age as fixed effect, and study center as random effects
Analyses for hormonal cancers were carried out in strata by gender. Bold font represents results that are statistically significant at p≤0.05
Because there were differences across the five centers with respect to study population, prevalence of G2019S mutation, and data collection procedures, we conducted a sensitivity analysis by excluding each center, one at a time, to determine the influence of study center on the associations between G2019S mutation and cancer outcomes (Table 4). The Sourasky Medical Center had the highest influence on the associations between LRRK2 mutation and cancers outcomes. When this center was excluded from analyses the ORs increased and became statistically significant for all cancers combined (OR, 1.84; 95%CI 1.15–2.94) and prostate cancer (OR, 3.06; 95%CI 1.29–7.28) in comparison with models that included all five centers or those that excluded the other four centers individually. For hormone-related cancers and breast cancers, although the ORs of different sensitivity analyses varied from 1.74 to 2.31 and from 2.37 to 3.39, respectively, all of the results were robust and statistically significant on each replication (p<0.05).
Table 4.
Sensitivity analysis of the influence of study center on association between LRRK2 G2019S mutation and cancer outcomes
| Sensitivity Analysis |
All Cancers Combined |
All Non-Skin Cancers |
Hormone-Related Cancers |
Breast Cancer (women) |
Prostate Cancer (men) |
|---|---|---|---|---|---|
| All Study Centers | |||||
| OR* | 1.49 | 1.57 | 2.06 | 2.88 | 2.05 |
| 95% CI | 0.99 – 2.24 | 1.04 – 2.38 | 1.22 – 3.47 | 1.39 – 5.98 | 0.92 – 4.55 |
| p-value | 0.057 | 0.034 | 0.007 | 0.004 | 0.08 |
| Excluding Sheba / Israel | |||||
| OR* | 1.59 | 1.51 | 2.27 | 3.39 | 2.08 |
| 95% CI | 0.97 – 2.60 | 0.92 – 2.47 | 1.20 – 4.28 | 1.49 – 7.74 | 0.82 – 5.27 |
| p-value | 0.06 | 0.1 | 0.012 | 0.004 | 0.12 |
| Excluding Sourasky / Israel | |||||
| OR* | 1.84 | 2.13 | 2.31 | 2.54 | 3.06 |
| 95% CI | 1.15 – 2.94 | 1.32 – 3.43 | 1.25 – 4.26 | 1.03 – 6.26 | 1.29 – 7.28 |
| p-value | 0.011 | 0.002 | 0.008 | 0.04 | 0.011 |
| Excluding Norway | |||||
| OR* | 1.35 | 1.44 | 1.74 | 2.37 | 1.84 |
| 95% CI | 0.88 – 2.06 | 0.94 – 2.22 | 1.00 – 3.04 | 1.09 – 5.12 | 0.79 – 4.27 |
| p-value | 0.17 | 0.09 | 0.05 | 0.03 | 0.16 |
| Excluding Spain | |||||
| OR* | 1.4 | 1.65 | 2.21 | 2.84 | 1.97 |
| 95% CI | 0.89 – 2.21 | 1.03 – 2.65 | 1.15 – 3.92 | 1.24 – 6.46 | 0.80 – 4.86 |
| p-value | 0.14 | 0.04 | 0.016 | 0.013 | 0.14 |
| Excluding US (NYC) | |||||
| OR* | 1.48 | 1.33 | 1.88 | 3.19 | 1.56 |
| 95% CI | 0.95 – 2.28 | 0.83 – 2.14 | 1.02 – 3.45 | 1.40 – 7.27 | 0.60 – 4.22 |
| p-value | 0.08 | 0.24 | 0.04 | 0.006 | 0.35 |
ORs and 95% CI presented for this analysis were estimated using mixed effect models adjusting for age as fixed effect, and study center as random effects.
Bold font represents results that are statistically significant at p<0.05
Discussion
In this pooled analysis we observed a 62% increased risk (95% CI, 1.04 – 2.52) for all non-skin cancers among LRRK2 G2019S mutation carriers in comparison with non-carriers in a large sample (N=1,549) of PD patients from five multinational centers. There was a statistically significant positive association for hormone-related cancers (OR, 1.87; p=0.03), which was driven mostly by breast cancer in women (OR, 2.34; p=0.04). However, there were no associations between G2019S mutations and smoking-related cancers or other types of cancer.
The underlying biological mechanism that links LRRK2 G2919S mutation and cancer, especially hormone–related cancers (eg, breast and prostate) remains largely unknown. The LRRK2 is a large protein that encodes two enzymatic functions, a protein kinase and a ras-oncogene like guanosine triphosphatase domain, as well as multiple protein interaction domains 14,16,27. The G2019S mutation has been shown15 to directly increase kinase activity resulting in a gain of function. Experimental studies27,28 have demonstrated that several mitogen-activated protein kinase kinases, which are known to reside alongside LRRK2 in the tyrosine kinase-like branch of the kinome, might be acting as LRRK2 substrates. Thus, it is possible that LRRK2 targets in vivo substrates through these mitogen-activated protein kinase docking sites and therefore may activate breast and prostate carcinogenesis through a mitogen-activated protein kinase signaling pathway 28. In addition, amplification and overexpression of the LRRK2 gene has been reported29 in other cancers, including papillary renal and thyroid carcinomas.
It is unclear whether the increased breast cancer risk associated with LRRK2 G2019S mutation is limited to PD patients. To address this issue, a large study30 in the United Kingdom genotyped 1,014 breast cancer cases and 1,033 controls without PD for G2019S mutations and found none. However, the prevalence of LRRK2 G2019S varies widely by population 17,18,23, and in the United Kingdom the frequency of this mutation is very low. Another investigation31 of 188 breast cancer-associated single-nucleotide polymorphisms from genome-wide association studies also did not find cosegregation with PD susceptibility loci, including LRRK2. By contrast, colon cancer appeared to be increased in LRRK2 R1441G/C mutation carriers without PD 21. Therefore, evaluation of asymptomatic LRRK2 carriers is needed to directly assess whether cancer segregates with LRRK2 mutations independent of PD.
Breast cancer and PD have been linked in several studies5,6,12. Among 426 Japanese PD patients there was an RR of 5.5 (95%CI, 1.1–16.03) for breast cancer in comparison with the general population; however, this finding was based on only three cases of breast cancer 12. In a Danish cohort of 14,088 PD patients, there was an RR of 1.24 (95%CI, 1.0–1.5) for breast cancer 5, which was maintained in an updated analysis6 that included 224 incident cases (RR, 1.17; 95%CI, 1.02–1.34). Some studies32,33 have suggested that an association between PD and breast cancer could be attributable to estrogens; however, the relationship between endogenous estrogens and PD is controversial 34.
Glucocerebrosidase (GBA1) mutations in the biallelic forms are associated with an increased risk of cancer, especially hematologic malignancy 35. Because GBA1 mutations have a founder effect in AJs and Spaniards36, the inclusion of GBA1 mutation carriers in the group of patients with PD who were not LRRK2 G2019S mutation carriers could potentially attenuate the difference in cancer rates between G2019S mutation carriers and non-carriers. Although we did not include GBA1 mutation carriers in the present analysis, it is likely that any effect is nondifferential, since GBA1 mutations do not modify the risk between LRRK2 mutations and PD 24.
Advantages of our study include the large sample size of 1,549 PD patients, as well as detailed collection of demographic characteristics, clinical characteristics, and cancer outcomes. Most non-skin cancers were verified and confirmed by medical records and tumor registry databases. One limitation of the study is that it was not a prospective cohort, but rather a cross-sectional analysis of data collected through five medical centers with some heterogeneity regarding data collection protocols as well as a potential for referral bias. In addition, the small number of some cancers (eg, kidney, hematologic/lymphoma, and bladder) limited the statistical power to investigate associations between LRRK2 mutations and rare cancers. Finally, we did not have information on hormonal and reproductive factors that could confound the association between LRRK2 mutations and breast cancer. Although we did not have complete information on the BRCA1/BRCA2 mutation status of all women with PD, investigators at Sheba Medical Center19 evaluated mutations in their breast cancer cases and found only a single BRCA1 mutation that cosegregated with the LRRK2 G2019S mutation. They separately analyzed genome-wide association study data evaluating breast cancer single-nucleotide polymorphisms in relationship to PD genes and found no suggestion of simple cosegregation or shared genetic loci 31. Thus, the association between LRRK2 G2019S mutation and breast cancer is unlikely to be the result of confounding by BRCA1/BRCA2 mutation-carrier status, but this cannot be fully ruled out without genotyping all breast cancer patients.
Although our sensitivity analyses demonstrated that the results were overall robust with removal of each center, we could not explain the lack of an association between non-skin cancers and G2019S mutations in two centers. One of the reasons could be the relative small number of breast cancer cases in each center, and therefore center-specific analyses were underpowered. We observed variability in LRRK2 G2019S mutation carriers by center, which was not entirely explained by differences in geography and ethnic backgrounds but could also be the result of ascertainment of PD patients or differences in data collection protocols. Therefore, to be more certain of the positive association between LRRK2 G2019S mutation and risks of non-skin cancers and breast cancer, larger prospective studies using the same instruments and protocols across sites are warranted. The limited evidence that breast cancer risk appears to be increased only among PD patients is enigmatic and requires rigorous investigation through family-based studies. Moreover, an investigation of the association between other LRRK2 mutations in relationship to cancer among PD patients is needed to understand the underlying genetic susceptibility.
Supplementary Material
Acknowledgment
We thank Dr. Chris Coffey for his advice on statistical analysis methods, and Robert Ortega for data analysis at Mount Sinai Beth Israel Medical Center. Drs. Ilir Agalliu and Rachel Saunders-Pullman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by the Michael J. Fox Foundation, and the National Institutes of Health (NIH) grant K02-NS073836 (to RSP). The funding agencies had no role in the design and conduct of the study; data collection, management, analysis, and interpretation of the data; as well as in preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Declaration on Interests: None
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