Neurology -- Correspondence for Inzelberg and Jankovic, 69 (15) 1542-1550

Correspondence published:

Are Parkinson disease patients protected from some but not all cancers?: Audrey J. Strongosky, Matthew Farrer and Zbigniew K. Wszolek (25 February 2008)

Reply from the authors: Rivka Inzelberg, Joseph Jankovic Baylor College of Medicine, Houston, TX (25 February 2008)

Are Parkinson disease patients protected from some but not all cancers? 25 February 2008

Audrey J. Strongosky,
Mayo Clinic Jacksonville
4500 San Pablo Road Jacksonville, FL 32224,
Matthew Farrer and Zbigniew K. Wszolek
Send Correspondence to journal:
Re: Are Parkinson disease patients protected from some but not all cancers?

strongosky.audrey2{at}mayo.edu Audrey J. Strongosky, et al.

We read the article by Inzelberg et al. with great interest. [1] We have followed a large family from Western Nebraska (Family D) with autosomal dominant Parkinson disease (PD) since 1992. The pedigree contains 190 individuals with 23 affected members spanning six generations. [2] The linkage studies demonstrated the presence of PARK8 parkinsonism (LRRK2, R1441C) in affected and in some asymptomatic family members.
There were eight diagnoses of cancer (pancreas, gall bladder, lung, testicular, and colon) in this family according to direct report and review of medical records. Of the 18 known mutation carriers in this family, [3] four have been diagnosed with colon cancer, and three of these developed in the ascending colon, specifically the ileocecal valve area. Only one of these mutation-positive patients has been diagnosed with PD, the other two remain asymptomatic mutation carriers. All three colon cancer patients had colon resections without need for chemotherapy or radiation. All have had at least two follow-up colonoscopies with no cancer recurrence.
There is little known about association of cancer with genetic forms of parkinsonism particularly with PARK8 parkinsonism. Therefore, this data may serve as a substrate for further investigations in this area. Perhaps LRRK2 gene expression is wider then initially anticipated. It is unclear whether more colon cancer or other types of cancer are present in this family.
We will continue our research on this and other PARK8 families. It may also be worthwhile to explore the presence of colon cancer in LRRK2 mice model.
References
1. Inzelberg, R, Jankovic, J. Are Parkinson disease patients protected from some but not all cancers? Neurology 69: 1542-1550.
2. Wszolek ZK, Pfeiffer RF, Tsuboi Y et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;62:1619-1622.
3. Zimprich A, Biskup S, Leitner P et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-607.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 25 February 2008

Rivka Inzelberg,
Sheba Medical Center, Tel Hashomer and Rappaport Faculty of Medicine
Tel Hashomer, Israel, 52621,
Joseph Jankovic Baylor College of Medicine, Houston, TX
Send Correspondence to journal:
Re: Reply from the authors

irivka{at}tx.technion.ac.il Rivka Inzelberg, et al.

We are grateful to Dr. Strongosky et al. for confirming that PD may be associated with some but not other cancers. [1] The authors observed several patients with cancers, particularly colon carcinoma, in a large pedigree with the LRRK2 mutation R1441C.
Strongosky et al. also consider the possible relationship between this gene and colon carcinoma and suggest, as we have observed, that the prognosis for these cancers may be favorable. A possible link between PD and cancer might be found in the autophagy-lysosome pathway, which plays a role in both disorders. [4]
Although the role of LRRK2 in cancer is unknown, there are two pathways responsible for cell survival that may involve products of genes associated with PD. These include the mitogen-activated protein kinases (MAPK) (Erk1/2) signaling pathway and the PI3K/Akt dependent pathway. The LRRK2 gene encodes a MAPKKK protein. [5,6] Unraveling the MAPK signal pathway in dopamine neurons and cancer cells may clarify the PD-cancer relationship and open a therapeutic window for cancer as well as PD therapy.
The search for possible co-morbidity between cancers and the PARK8 gene may provide insight into the pathogenesis of both disorders. Since the publication of our paper, two studies have been published supporting our findings. [1] A case-controlled, prospective study of 22,071 US male physicians, followed for 22 years during which time 487 incident cases of PD were identified, showed an inverse relationship between cancers (both smoking-related and non-smoking-related) and the subsequent development of PD. [7]
Another large study in Denmark involving 14,088 patients diagnosed with PD confirmed markedly increased risk for malignant melanoma in this population, but there is no evidence that treatment with levodopa increases the risk. [8]
Unraveling the relationship between PD and cancers is an emerging area of research.
References
4. Pan T, Kondo S, Le W, Jankovic J. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson�s disease. Brain 2008 (in press).
5. Deng H, Le W, Guo Y, et al. Genetic analysis of LRRK2 mutations in patients with Parkinson disease. J Neurol Sci. 2006;251:102-106.
6. Tomiyama H, Li Y, Funayama M, et al. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Mov Disord 2006;12:1102-1108.
7. Driver JA, Kurth T, Buring JE, Gaziano JM, Logroscino G. Prospective case-control study of nonfatal cancer preceding the diagnosis of Parkinson's disease. Cancer Causes Control 2007;18:705-711.
8. Olsen JH, Tangerud K, Wermuth L, Frederiksen K, Friis S. Treatment with levodopa and risk for malignant melanoma. Mov Disord 2007;22:1252-1257.
Disclosures: The authors report no conflicts of interest.