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LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease

Rachel Saunders-Pullman1, Matthew J Barrett, Kaili M Stanley

  • 1Department of Neurology, Beth Israel Medical Center, New York, New York, USA. rsaunder@bethisraelny.org

Movement Disorders : Official Journal of the Movement Disorder Society
|September 7, 2010
PubMed

Insights

Leucine rich repeat kinase (LRRK2) G2019S mutation carriers show a nearly threefold increased risk of nonskin cancers. This suggests a potential link between LRRK2 gain of function and cancer development, warranting further investigation.

Area of Science:

  • Neurogenetics
  • Oncology
  • Molecular Biology

Background:

  • Leucine rich repeat kinase (LRRK2) G2019S mutations are implicated in Parkinson's disease (PD) pathogenesis via a toxic gain of function.
  • Small molecule kinase inhibitors, some used in cancer therapy, may inhibit LRRK2.
  • Limited data exists on cancer risk in LRRK2 mutation carriers.

Purpose of the Study:

  • To investigate the association between LRRK2 G2019S mutations and the risk of developing cancer.
  • To evaluate cancer incidence and timing relative to PD onset in LRRK2 mutation carriers.

Main Methods:

  • Retrospective chart review of 163 unrelated Ashkenazi Jewish Parkinson's disease patients.
  • Analysis of cancer history, including type and age at diagnosis, from baseline intake and follow-up visits.
  • Comparison of cancer risk between LRRK2 G2019S mutation carriers and non-carriers.

Main Results:

  • LRRK2 G2019S carriers exhibited a nearly threefold increased risk of nonskin cancers (HR 2.9, 95% CI 1.3-6.6).
  • Nonskin cancers occurred earlier in LRRK2 carriers (mean age 56.0) compared to non-carriers (mean age 62.0), though not statistically significant.
  • A higher proportion of LRRK2 carriers (67%) developed cancer before PD onset versus non-carriers (40%).

Conclusions:

  • Findings suggest an elevated risk of nonskin cancers in individuals with LRRK2 G2019S mutations.
  • The increased cancer risk may be linked to the toxic gain of function associated with mutated LRRK2.
  • Further research is warranted to confirm these findings and elucidate the underlying mechanisms.

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