In Small Study, Parkinson's Disease Patients with LRRK2 Mutation Have Elevated Risk for Different Cancers

By Jamie Talan

September 19, 2019

A multicenter team of scientists have identified an almost five to 10-fold increased risk of leukemia, and a 2.3-fold increased risk of colon cancer in patients with Parkinson's disease (PD) who carry the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (from two separate analyses).

They also found an almost two-fold higher risk of skin cancer in LRRK2-PD patients compared with those with idiopathic PD and age-matched controls. The findings were published online July 26 in Movement Disorders.

The discovery of a link between cancer and Parkinson's disease is not new, but the findings from several epidemiological studies have been mixed, and they were generally too small in number to make clear cut recommendations.

This study includes assessments from information gathered on 2,365 Parkinson's patients, however, and the implications are this: People with the LRRK2 G2019S mutation do have a substantially higher risk for certain cancers and neurologists should take this into account when managing their patient's medical needs.

“We might consider that if someone is a carrier of the LRRK2 G2019S mutation they should be closely monitored for Parkinson's and for certain cancers,” said Ilir Agalliu, MD, PhD, associate professor in the department of epidemiology and population health at Albert Einstein College of Medicine, which collaborated with other medical centers in New York, California, Israel, Spain, and Germany.

Dr. Agalliu, a cancer epidemiologist, said that previous studies have identified a relationship between PD and cancer, and the findings have generally pointed to a decreased cancer risk in smoking-related cancers and other cancers, with the exception of a higher risk for melanoma.

But the numbers didn't seem to add up for people with the LRRK2 mutations, and a small number of studies were suggesting a higher signal for non-skin cancers and breast cancers.

Dr. Agalliu and senior author Rachel Saunders-Pullman, MD, MPH, the Bachmann-Strauss professor and associate professor of neurology at the Icahn School of Medicine at Mount Sinai and chief of movement disorders at Mount Sinai Beth Israel, and their colleagues were funded by the Michael J Fox Foundation to collaborate with other MJFF LRRK2 consortium sites to look further into this association.

Their previous work included a meta-analysis of 1,549 patients, in which 11.4 percent were LRRK2 G2019S carriers. They found a 62 percent increased risk of nonskin cancer and a two- to three-fold higher risk for hormone-related cancers, mostly breast cancer, compared with patients with idiopathic PD. That association made them wonder how these numbers would compare with people without PD and without the G2019S mutation.

“The association between skin cancer and the LRRK2 mutation in Parkinson's highlights one of the most consistent cancer associations in Parkinson's,” said Dr. Saunders-Pullman.

“Parkinson's disease patients, whether they have a LRRK2 mutation or not, have generally been shown to have a higher rate of skin cancer, especially melanoma. Because skin cancer may be treatable if captured early, it is very important to counsel patients on the need for yearly, or possibly more frequent, skin examinations, and the need to seek medical attention for any suspicious moles,” she said.

Study Methods, Findings

The scientists looked at cancer outcomes via questionnaires in 257 PD patients with the LRRK2 mutation, 712 idiopathic PD patients, and 218 controls recruited from seven LRRK2 consortium centers.

They sent out a detailed health questionnaire that included information on demographics, lifestyle, and reproductive factors; self-reported cancer history; personal health-related histories; and family histories of PD and cancer. Everyone was tested for LRRK2-G2019S mutations. (Two centers in Germany and Spain also tested for other LRRK2 mutations: R1441G/C and I2020T, but this analysis only included the G2019S carriers.)

Overall, cancer prevalence was similar in all groups, including controls: LRRK2-PD patients (32.3 percent), idiopathic PD patients (27.5 percent), and controls (27.5 percent). But patients with LRRK2-PD had a 4.55 greater risk of leukemia and a 1.61 increased risk for skin cancer.

When compared with idiopathic PD patients and controls, the LRRK2-PD patients also reported a higher proportion of multiple cancers: 8.6 percent compared with 6.6 percent in idiopathic PD patients and 3.7 percent in controls.

The scientists pooled the current data with previous findings from a 2015 JAMANeurology study, and they examined cancer risk in 401 LRRK2-PD and 1946 idiopathic PD patients. When the numbers increased in the pooled analysis, they found an even greater risk of leukemia in LRRK2-PD patients: almost ten times higher.

The researchers noted however that there were only five cases of leukemia in the LRRK2-PD patient group compared with no cases in the idiopathic PD group or controls. They also reported a 2.34 higher risk of colon cancer. These studies represent the largest cohort of PD patients with genetic screening for LRRK2 mutations.

The researchers also looked at whether the association between the cancer risks in the LRRK2 G2019S mutation varied by ethnicity. About 75 percent of the study participants were of Ashkenazi Jewish ancestry and the results were similar among different ethnicities, they said.

The authors said that one of the study limitations is that these were self-reported cancers and their answers were not validated with cancer registries or medical records in all participating centers. They also did not have information on the stage or severity of the cancers.

“This very large multisite and multinational study supports an association between certain rare cancers and LRRK2 mutation Parkinson disease, in particular, blood related cancers,” said Dr. Saunders-Pullman. “It is hoped that, in the future, potential shared mechanisms may be elucidated, and that if low side effect therapeutics are available for one, they might be applicable for the other.

“We did not replicate an association with hormonal cancers, which was seen in our earlier study, and also reported by others,” Dr. Saunders-Pullman continued. “This underscores that the frequency of different cancers was different across specific sites, and while we were able to assess across a wider range of participants, there will be not only individual but ethnic and region specific differences.”

So why would the LRRK2 G2019S mutation lead to an increase in certain cancers?

“The biological mechanism is not fully understood,” said Dr. Agalliu. He said he suspects that “the LRRK2 gene has a lot of domains and some regulate the MAP kinase pathway that is usually activated in cancer. The LRRK2 mutations could also activate several other cancer pathways.”

The implications of the findings, he added, is that “we might consider closely monitoring people with this LRRK2 mutation for PD and for certain cancers.”

He and his colleagues are interested in looking at other mutations along the LRRK2 gene to see if there are other cancer risks. “In epidemiology, we like when we see consistency of patterns, and yes, we saw something. It is important to validate these studies,” he added.

Expert Commentary

There are multiple intriguing links between PD and cancer, particularly for melanoma, said Clemens R. Scherzer, MD, professor of neurology at Harvard Medical School, director of the Advanced Center for Parkinson's Disease Research, and director of the precision neurology program at Brigham & Women's Hospital.

“This study claims a potential associations between PD patients carrying the G2019S LRRK2 mutation and leukemia. Subset analyses point at possible signals for associations also with nonmelanoma skin cancer and colon cancer. This is intriguing and will inspire further work.”

“To identify and characterize LRRK2-positive patients around the globe is a huge endeavor. However, the main findings are preliminary, based on just five LRRK2-PD patients who reported leukemia,” Dr. Scherzer said.

“The risk for cancer in patients with LRRK2-PD will need evaluation in larger, prospective, and population-based cohorts before clinical recommendations can be made. The study is limited in sample size and vulnerable to false positives due to the multiple testing, confounders, and potential threats from recruitment and ascertainment bias.”

“This is another study from a group of investigators with a strong track record in LRRK2 and cancer. The results are overall consistent with their previous findings that LRRK2 is associated with certain cancers,” said Xiqun Chen, MD, PhD, assistant professor of neurology at Massachusetts General Hospital.

“It is important to further investigate whether LRRK2 is a causal contributor to these cancers. Biologically, LRRK2 can activate MEK-ERK-MAPK and AKT-4E-BP1, which mediate cell survival and proliferation. And structurally, the LRRK2 kinase domain shares similarity with the oncogene BRAF. Some cancers harbor somatic LRRK2 mutations. Better understanding of the biology would provide valuable insight into specific cellular contexts in determining cells' final fate in response to a common pathogenic factor (LRRK2 G2019S).”

“The study provides evidence to inform a personalized medicine approach to screen LRRK2 mutation carriers for early detection for cancer,” she added. Dr. Chen became interested in the association between Parkinson's and cancer about five years ago, and her lab is now focusing on studying why these connections occur. She recently organized a meeting in Boston to bring together neurologists and cancer specialists to begin a discussion and educate specialists in both fields.

Disclosures

Drs. Agalliu and Chen had no conflicts of interest. Dr. Scherzer has collaborated with Pfizer, OPKO, Proteome Sciences, Sanofi, and Berg Health; has consulted for Sanofi; has served as advisor to the Michael J. Fox Foundation, NIH, Department of Defense; is on the scientific advisory board of the American Parkinson Disease Association; has received funding from the NIH, the US Department of Defense, the Harvard NeuroDiscovery Center, the Michael J. Fox Foundation, and American Parkinson Disease Association

https://journals.lww.com/neurotodayonline/Fulltext/2019/09190/In_Small_Study,_Parkinson_s_Disease_Patients_with.1.aspx