title: LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease.
abstract: Leucine rich repeat kinase (LRRK2) G2019S mutations are presumed to cause PD through a toxic gain of function of the protein kinase. Small molecule kinase inhibitors have been developed for the treatment of certain cancers, and some antioncogenic agents such as sunitinib, may nonspecifically inhibit LRRK2. Few studies, however, have assessed cancer risk in LRRK2 mutation carriers. To explore this risk, we evaluated records of Ashkenazi Jewish (AJ) PD patients participating in genetic research. Charts were reviewed for 163 unrelated AJ PD patients, 31 of whom harbored the G2019S mutation. History of cancer was queried at baseline intake using a form reviewing medical conditions, and charts were reviewed for all follow-up visits. 9/31 LRRK2 G2019S mutation carriers had nonskin cancers, whereas 15/132 without mutations had nonskin cancers, representing an almost threefold increased risk in this group (HR 2.9, 95% CI 1.3-6.6). Age at first nonskin cancer was younger in the LRRK2 carriers (56.0 years) than the noncarriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of noncarriers developed their first nonskin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of nonskin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2.
authors.affiliation: Department of Neurology, Beth Israel Medical Center, New York, New York, USA. rsaunder@bethisraelny.org
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Barrett
authors.forename: Kaili M
authors.initials: KM
authors.lastname: Stanley
authors.forename: Marta San
authors.initials: MS
authors.lastname: Luciano
authors.forename: Vicki
authors.initials: V
authors.lastname: Shanker
authors.forename: Lawrence
authors.initials: L
authors.lastname: Severt
authors.forename: Ann
authors.initials: A
authors.lastname: Hunt
authors.forename: Deborah
authors.initials: D
authors.lastname: Raymond
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.forename: Susan B
authors.initials: SB
authors.lastname: Bressman
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007585:Jews / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000150:complications / Q000235:genetics*; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk; D018709:Statistics, Nonparametric
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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