LETTERS:
NEW
LRRK2-G2019S Mutation Is Not Associated With an Increased Cancer Risk: A Kin-Cohort Study Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of autosomal dominant Parkinson’s disease (PD). G2019S mutation in this gene has been detected worldwide, with higher frequency in North-African and Ashkenazi Jewish populations. LRRK2 is a protein of unknown function that has been linked to other human diseases, including inflammatory bowel disease and cancer.1 An increased risk of non–skin cancer in LRRK2G2019S carriers was reported in the Ashkenazi Jewish population.2,3 However, recently no increased association between LRRK2 mutations R1441G and G2019S and any type of cancer was found in a Basque population of PD, suggesting that further studies are needed.4 We studied our Italian population to evaluate whether LRRK2 mutations increase cancer risk. We compared prevalence of cancer in PD LRRK2-carriers and a group of patients with idiopathic PD without LRRK2 mutations (case-control ratio 5 1:2 matched for sex, age 6 2 years, and disease duration 6 2 years). In addition, we estimated prevalence of cancer in all first-degree relatives of the two groups (regardless of the presence or absence of PD) through kincohort analysis, which evaluates the cumulative risk of disease in probands’ relatives according to Mendelian inheritance patterns and regardless of genetic testing results.5 The cumulative probability of developing cancer in PD patients (carrier and non-carrier) was estimated using Kaplan-Meier analysis, and a log-rank test was performed. The cumulative probability of developing cancer in firstdegree relatives was estimated by kin-cohort approach using the open-source statistical computing environment R. Forty LRRK2-carriers were identified through the analysis of 2,523 unrelated consecutive PD patients of Italian origin.6 We researched the presence of cancer in the probands and in the first-degree relatives (type of cancer, age at onset, age at death) during medical examination or through telephone interview with the proband or an informed caregiver. No medical records were reviewed. We were able to contact 30 carriers (G2019S, N 5 26; R1441C, N 5 3; R1441H, N 5 1) (mean age at last exami-
O B S E RVAT I O N S
nation/contact, 67 6 9.0 years) and 60 matched non-carriers (mean age, 68 6 9.6 years). Of the other 10, eight were deceased and two were lost to follow-up. The first-degree relatives included in the analysis were N 5 225 for the carrier group (mean age, 60 6 19.2 years) and N 5 377 for the non-carrier group (mean age, 61 6 19.3). Results are reported in Table 1. No significant differences in cancer prevalence were found between carriers and noncarriers, in particular considering the G2019S mutation. Of the 30 LRKK2-carriers probands, only two had a cancer: one prostatic carcinoma in a G2019S-carrier and one gastric cancer in a R1441C-carrier, both developed after PD onset. Of the 225 first-degree LRRK2-carriers’ relatives, 21 had a malignancy, but none of them was affected by PD or other neurodegenerative disease. Only one melanoma was reported in the controls’ relatives group. Our data do not support an association between LRRK2G2019S mutation and an increased cancer risk. Possibly this association is limited to certain populations (i.e., Ashkenazi Jew) because of concomitant predisposing factors, but not in others. Interestingly, one R1441C carrier had a gastrointestinal cancer (stomach), and colon carcinomas were previously described in a large R1441C family.7 Roberta Allegra, MD,1 Sara Tunesi, PhD,2 Roberto Cilia, MD,1 Gianni Pezzoli, MD,1 and Stefano Goldwurm, MD, PhD1 1
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy 2 Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, University “Amedeo Avogadro” of Piemonte Orientale, Novara, Italy
References 1.
Lewis PA, Alessi DR. Deciphering the function of leucine-rich repeat kinase 2 and targeting its dysfunction in disease. Biochem Soc Trans 2012;40:1039-1041.
2.
Saunders-Pullman R, Barrett MJ, Stanley KM, et al. LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov Disord 2010;25:2536-2541.
3.
Inzelberg R, Cohen OS, Aharon-Peretz J, et al. The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers. Neurology 2012;78:781-786.
4.
*Correspondence to: Stefano Goldwurm, Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1 - 20126 Milano, Italy, E-mail: [email protected]
Ruiz-Martınez J, de la Riva P, Rodrıguez-Oroz MC, et al. Prevalence of cancer in Parkinson’s disease related to R1441G and G2019S mutations in LRRK2. Mov Disord 2014;29:750-755.
5.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
Goldwurm S, Tunesi S, Tesei S, et al. Kin-cohort analysis of LRRK2-G2019S penetrance in Parkinson’s disease. Mov Disord 2011;26:2144-2145.
6.
Cilia R, Siri C, Rusconi D, et al. LRRK2 mutations in Parkinson’s Disease: confirmation of a gender effect in the Italian population. Parkinsonism Relat Disord 2014 Apr 25. [cited 14 July 2014]. Available from: http://dx.doi.org/10.1016/j.parkreldis.2014.04.016.
7.
Strongosky AJ, Farrer M, Wszolek ZK. Are Parkinson disease patients protected from some but not all cancers? Neurology 2008; 71:1650.
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Received: 19 March 2014; Revised: 5 June 2014; Accepted: 16 June 2014 Published online 22 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25969
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TABLE 1. Cancer frequency and lifetime risk in LRRK2-carrier and non-carrier
Probandsa
All LRRK2 mutations
Relativesb
Only LRRK2G2019S
Probandsa
Relativesb
Probability of Cancer at 80 y (95%CI)
Pc
0.57
M/F
Cancer/ Subjects (%)
LRRK2-carriers
11/19
2/30 (6.6)
0.16 (0.04-0.50)
Non-carrier
22/38
6/60 (10)
0.12 (0.05-0.25)
LRRK2-carriers
108/117
21/225 (9.3)
0.11 (0.02-0.28)
Non-carriers
184/193
55/377 (14.6)
0.26 (0.19-0.33)
G2019S-carriers
10/16
1/26 (3.8)
0.07 (0.01-0.39)
Non-carriers
19/33
5/52 (9.6)
0.11 (0.05-0.26)
G2019S-carriers
91/104
19/195 (9.7)
0.14 (0.03-0.32)
Non-carriers
159/171
47/330 (14.2)
0.26 (0.18-0.33)
a
Type of Cancer
1 stomach, 1 prostate. 2 colon, 2 breast, 1 reproductive, 1 skin (basal cell carcinoma).
0.19
3 breast, 2 stomach, 2 pharynx, 2 colon, 2 hematologic, 2 reproductive, 1 bladder, 1 kidney, 1 prostate, 1 lung, 1 pleura, 1 pancreas, 1 hypophysis, 1 skin (basal cell carcinoma). 10 breast, 8 stomach, 7 lung, 4 colon, 4 pancreas, 4 prostate, 3 liver, 3 brain, 2 reproductive, 2 hematologic, 2 esophagus, 2 pharynx, 1 myeloma, 1 thyroid, 1 kidney, 1 skin (melanoma).
0.37
1 prostate 2 colon, 1 breast, 1 reproductive, 1 skin (basal cell carcinoma).
0.44
3 breast, 2 stomach, 2 hematologic, 2 colon, 2 pharynx, 1 bladder, 1 reproductive, 1 kidney, 1 lung, 1 pleura, 1 pancreas, 1 hypophysis, 1 skin (basal cell carcinoma). 9 breast, 6 stomach, 5 lung, 4 colon, 4 pancreas, 4 prostate, 2 liver, 2 brain, 2 esophagus, 2 hematologic, 1 reproductive, 1 pharynx, 1 myeloma, 1 thyroid, 1 kidney, 1 skin (melanoma).
Kaplan-Meier analysis. Kin-cohort analysis. c All P values are nonsignificant. We repeated the statistical analysis excluding the 3 skin cancers (one melanoma in a control’s relative, and two basal cell carcinomas—one in a non-carrier proband, the other in a carrier’s relative): all P values were still nonsignificant (data not shown). Subjects were analyzed according to sex, but all P values were still nonsignificant (data not shown). b
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Movement Disorders, Vol. 29, No. 10, 2014
NEW
LRRK2-G2019S Mutation Is Not Associated With an Increased Cancer Risk: A Kin-Cohort Study Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of autosomal dominant Parkinson’s disease (PD). G2019S mutation in this gene has been detected worldwide, with higher frequency in North-African and Ashkenazi Jewish populations. LRRK2 is a protein of unknown function that has been linked to other human diseases, including inflammatory bowel disease and cancer.1 An increased risk of non–skin cancer in LRRK2G2019S carriers was reported in the Ashkenazi Jewish population.2,3 However, recently no increased association between LRRK2 mutations R1441G and G2019S and any type of cancer was found in a Basque population of PD, suggesting that further studies are needed.4 We studied our Italian population to evaluate whether LRRK2 mutations increase cancer risk. We compared prevalence of cancer in PD LRRK2-carriers and a group of patients with idiopathic PD without LRRK2 mutations (case-control ratio 5 1:2 matched for sex, age 6 2 years, and disease duration 6 2 years). In addition, we estimated prevalence of cancer in all first-degree relatives of the two groups (regardless of the presence or absence of PD) through kincohort analysis, which evaluates the cumulative risk of disease in probands’ relatives according to Mendelian inheritance patterns and regardless of genetic testing results.5 The cumulative probability of developing cancer in PD patients (carrier and non-carrier) was estimated using Kaplan-Meier analysis, and a log-rank test was performed. The cumulative probability of developing cancer in firstdegree relatives was estimated by kin-cohort approach using the open-source statistical computing environment R. Forty LRRK2-carriers were identified through the analysis of 2,523 unrelated consecutive PD patients of Italian origin.6 We researched the presence of cancer in the probands and in the first-degree relatives (type of cancer, age at onset, age at death) during medical examination or through telephone interview with the proband or an informed caregiver. No medical records were reviewed. We were able to contact 30 carriers (G2019S, N 5 26; R1441C, N 5 3; R1441H, N 5 1) (mean age at last exami-
O B S E RVAT I O N S
nation/contact, 67 6 9.0 years) and 60 matched non-carriers (mean age, 68 6 9.6 years). Of the other 10, eight were deceased and two were lost to follow-up. The first-degree relatives included in the analysis were N 5 225 for the carrier group (mean age, 60 6 19.2 years) and N 5 377 for the non-carrier group (mean age, 61 6 19.3). Results are reported in Table 1. No significant differences in cancer prevalence were found between carriers and noncarriers, in particular considering the G2019S mutation. Of the 30 LRKK2-carriers probands, only two had a cancer: one prostatic carcinoma in a G2019S-carrier and one gastric cancer in a R1441C-carrier, both developed after PD onset. Of the 225 first-degree LRRK2-carriers’ relatives, 21 had a malignancy, but none of them was affected by PD or other neurodegenerative disease. Only one melanoma was reported in the controls’ relatives group. Our data do not support an association between LRRK2G2019S mutation and an increased cancer risk. Possibly this association is limited to certain populations (i.e., Ashkenazi Jew) because of concomitant predisposing factors, but not in others. Interestingly, one R1441C carrier had a gastrointestinal cancer (stomach), and colon carcinomas were previously described in a large R1441C family.7 Roberta Allegra, MD,1 Sara Tunesi, PhD,2 Roberto Cilia, MD,1 Gianni Pezzoli, MD,1 and Stefano Goldwurm, MD, PhD1 1
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy 2 Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, University “Amedeo Avogadro” of Piemonte Orientale, Novara, Italy
References 1.
Lewis PA, Alessi DR. Deciphering the function of leucine-rich repeat kinase 2 and targeting its dysfunction in disease. Biochem Soc Trans 2012;40:1039-1041.
2.
Saunders-Pullman R, Barrett MJ, Stanley KM, et al. LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov Disord 2010;25:2536-2541.
3.
Inzelberg R, Cohen OS, Aharon-Peretz J, et al. The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers. Neurology 2012;78:781-786.
4.
*Correspondence to: Stefano Goldwurm, Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1 - 20126 Milano, Italy, E-mail: [email protected]
Ruiz-Martınez J, de la Riva P, Rodrıguez-Oroz MC, et al. Prevalence of cancer in Parkinson’s disease related to R1441G and G2019S mutations in LRRK2. Mov Disord 2014;29:750-755.
5.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
Goldwurm S, Tunesi S, Tesei S, et al. Kin-cohort analysis of LRRK2-G2019S penetrance in Parkinson’s disease. Mov Disord 2011;26:2144-2145.
6.
Cilia R, Siri C, Rusconi D, et al. LRRK2 mutations in Parkinson’s Disease: confirmation of a gender effect in the Italian population. Parkinsonism Relat Disord 2014 Apr 25. [cited 14 July 2014]. Available from: http://dx.doi.org/10.1016/j.parkreldis.2014.04.016.
7.
Strongosky AJ, Farrer M, Wszolek ZK. Are Parkinson disease patients protected from some but not all cancers? Neurology 2008; 71:1650.
------------------------------------------------------------
Received: 19 March 2014; Revised: 5 June 2014; Accepted: 16 June 2014 Published online 22 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25969
Movement Disorders, Vol. 29, No. 10, 2014
1325
A L L E G R A
E T
A L
TABLE 1. Cancer frequency and lifetime risk in LRRK2-carrier and non-carrier
Probandsa
All LRRK2 mutations
Relativesb
Only LRRK2G2019S
Probandsa
Relativesb
Probability of Cancer at 80 y (95%CI)
Pc
0.57
M/F
Cancer/ Subjects (%)
LRRK2-carriers
11/19
2/30 (6.6)
0.16 (0.04-0.50)
Non-carrier
22/38
6/60 (10)
0.12 (0.05-0.25)
LRRK2-carriers
108/117
21/225 (9.3)
0.11 (0.02-0.28)
Non-carriers
184/193
55/377 (14.6)
0.26 (0.19-0.33)
G2019S-carriers
10/16
1/26 (3.8)
0.07 (0.01-0.39)
Non-carriers
19/33
5/52 (9.6)
0.11 (0.05-0.26)
G2019S-carriers
91/104
19/195 (9.7)
0.14 (0.03-0.32)
Non-carriers
159/171
47/330 (14.2)
0.26 (0.18-0.33)
a
Type of Cancer
1 stomach, 1 prostate. 2 colon, 2 breast, 1 reproductive, 1 skin (basal cell carcinoma).
0.19
3 breast, 2 stomach, 2 pharynx, 2 colon, 2 hematologic, 2 reproductive, 1 bladder, 1 kidney, 1 prostate, 1 lung, 1 pleura, 1 pancreas, 1 hypophysis, 1 skin (basal cell carcinoma). 10 breast, 8 stomach, 7 lung, 4 colon, 4 pancreas, 4 prostate, 3 liver, 3 brain, 2 reproductive, 2 hematologic, 2 esophagus, 2 pharynx, 1 myeloma, 1 thyroid, 1 kidney, 1 skin (melanoma).
0.37
1 prostate 2 colon, 1 breast, 1 reproductive, 1 skin (basal cell carcinoma).
0.44
3 breast, 2 stomach, 2 hematologic, 2 colon, 2 pharynx, 1 bladder, 1 reproductive, 1 kidney, 1 lung, 1 pleura, 1 pancreas, 1 hypophysis, 1 skin (basal cell carcinoma). 9 breast, 6 stomach, 5 lung, 4 colon, 4 pancreas, 4 prostate, 2 liver, 2 brain, 2 esophagus, 2 hematologic, 1 reproductive, 1 pharynx, 1 myeloma, 1 thyroid, 1 kidney, 1 skin (melanoma).
Kaplan-Meier analysis. Kin-cohort analysis. c All P values are nonsignificant. We repeated the statistical analysis excluding the 3 skin cancers (one melanoma in a control’s relative, and two basal cell carcinomas—one in a non-carrier proband, the other in a carrier’s relative): all P values were still nonsignificant (data not shown). Subjects were analyzed according to sex, but all P values were still nonsignificant (data not shown). b
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