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 non-skin cancers, whereas 15/132 without mutations had non-skin cancers, representing an almost three-fold increased risk in this group (HR 2.9, 95% CI 1.3-6.6). Age at first non-skin cancer was younger in the LRRK2 carriers (56.0 years) than the non-carriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of non-carriers developed their first non-skin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of non-skin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2.

Differential risks of cancer types in people with Parkinson’s disease: A national record-linkage study

“…Recently, LRRK2 mutations have been found to be an important risk factor for sporadic and familial PD [24,25]. It has been shown that PD patients with LRRK2 mutations have a different profile of malignancy compared with non-carriers of LRRK2 gene mutations [26,27]. Mutation carriers had a particularly increased risk of breast cancer in both studies, and might explain part of the increased rate in breast cancer in PD patients that we and others find [2,3].…”

Higher Frequency of Certain Cancers inLRRK2G2019S Mutation Carriers With Parkinson Disease

“…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.…”

Cancer and Neurodegeneration: Between the Devil and the Deep Blue Sea

“…The PINK1 and LRRK2 somatic mutations identified in cancer were all heterozygous and their pathological effect remains to be determined. The prevalence of LRRK2 G2019S (the most common genetic determinant of PD) is not increased in patients with melanoma [7], [54], but a recent study showed an almost 3-fold increased risk of non-skin cancers in LRRK2 G2019S mutation carriers [55]. Moreover, of the 18 known mutation carriers of a large family with LRRK2 R1441C parkinsonism, four had colon cancer [56].…”