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. 2020 Jul 24;11(8):846.
doi: 10.3390/genes11080846.

Comprehensive Genomic Analysis Reveals the Prognostic Role of LRRK2 Copy-Number Variations in Human Malignancies

Gianluca Lopez  1   2 , Giulia Lazzeri  3   4   5 , Alessandra Rappa  6 , Giuseppe Isimbaldi  7 , Fulvia Milena Cribiù  1 , Elena Guerini-Rocco  6   8 , Stefano Ferrero  1   9 , Valentina Vaira  1 , Alessio Di Fonzo  3   4
Affiliations

Comprehensive Genomic Analysis Reveals the Prognostic Role of LRRK2 Copy-Number Variations in Human Malignancies

Gianluca Lopez et al. Genes (Basel). .

Abstract

Genetic alterations of leucine-rich repeat kinase 2 (LRRK2), one of the most important contributors to familial Parkinson's disease (PD), have been hypothesized to play a role in cancer development due to demographical and preclinical data. Here, we sought to define the prevalence and prognostic significance of LRRK2 somatic mutations across all types of human malignancies by querying the publicly available online genomic database cBioPortal. Ninety-six different studies with 14,041 cases were included in the analysis, and 761/14,041 (5.4%) showed genetic alterations in LRRK2. Among these, 585 (76.9%) were point mutations, indels or fusions, 168 (22.1%) were copy number variations (CNVs), and 8 (1.0%) showed both types of alterations. One case showed the somatic mutation R1441C. A significant difference in terms of overall survival (OS) was noted between cases harboring somatic LRRK2 whole deletions, amplifications, and CNV-unaltered cases (median OS: 20.09, 57.40, and 106.57 months, respectively; p = 0.0008). These results suggest that both LRRK2 amplifications and whole gene deletions could play a role in cancer development, paving the way for future research in terms of potential treatment with LRRK2 small molecule inhibitors for LRRK2-amplified cases.

Keywords: CNV; LRRK2; cancer; mutations; prognostic.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prevalence and distribution of LRRK2 genetic alterations across the analyzed studies. The 5% of the first and second row is expanded to better visualize the data [48,49,50].
Figure 2
Figure 2
LRRK2 alteration frequency across cancer types. The types of alterations are color-coded as shown in the legend above [48,49,50].
Figure 3
Figure 3
LRRK2 missense, truncating, and inframe mutations in the studies analyzed. A scattered mutational distribution is evident. The alterations are color-coded as shown in the legend above [48,49,50].
Figure 4
Figure 4
Overall survival of LRRK2 altered (MUT and/or CNV) vs. LRRK2 non-altered cases. A slightly worse prognosis can be observed for altered cases [48,49,50]. MUT: point mutations, indels and fusions; CNV: copy-number variations.
Figure 5
Figure 5
Overall survival of LRRK2 altered (MUT and/or CNV) vs. LRRK2 non-altered cases in prostatic adenocarcinoma (A) and endometrial carcinoma (B). The prognostic significance of LRRK2 altered cases is negative for prostatic cancer and positive for endometrial cancer [48,49,50]. MUT: point mutations, indels and fusions; CNV: copy-number variations.
Figure 6
Figure 6
Prognostic significance of LRRK2 CNV-altered vs. CNV-unaltered cases (A) and in MUT-altered vs. MUT-unaltered cases (B). A significant difference is noted for cases analyzed for CNVs, but not for cases profiled for MUTs [48,49,50]. MUT: point mutations, indels and fusions; CNV: copy-number variations.
Figure 7
Figure 7
Survival of cases showing LRRK2 whole gene deletions (DEL, orange curve), amplifications (AMP, green curve), and no copy-number alterations (0, blue curve).
See this image and copyright information in PMC

References

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