A recurrent mutation in PARK2 is associated with familial lung cancer

Abstract

PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.

Figure 1

Filtering Strategy in Family A for the Three NSCLC Individuals Subjected to Exome Sequencing The filtering criteria are written on the left side of the workflow. The number of variants that remained after each filtering step is shown in the workflow.

Figure 2

Sanger Sequencing Chromatograms of the PARK2 Mutation and the Plot of the Resulting Amino Acid Change in the PARK2 Domain The top panel shows the sequencing chromatograms of the PARK2 germline mutation c.823C>T for the three probands in family A, and the bottom panel presents the schematic plot of PARK2 domains and the amino acid change (p.Arg275Trp) resulting from c.823C>T. Chromatograms of both forward and reverse sequences are given, and the complementary-strand alleles (G>A) are shown. The solid red arrowhead shows the location of the resulting amino acid change in PARK2.

Figure 3

The PARK2 c.823C>T (p.Arg275Trp) Mutation in Four Lung-Cancer-Affected Families Basic annotations are as follows: the black filled symbols indicate lung-cancer-affected individuals; an oblique line shows deceased family members; the numbers ending with “ y” under each symbol indicate the age at diagnosis (affected individuals) or last contact (control individuals); “Smk” means a current or former smoker; “Nev” indicates someone who never smoked; “c.823C>T” indicates a subject with the heterozygous c.823C>T (p.Arg275Trp) mutation; and “WT” indicates a subject with wild-type alleles at this locus. In family A, five lung-cancer-affected subjects (III-1, III-4, III-7, III-10, and IV-18 [black filled symbols]; age at onset ranging from 38 to 69 years) without SCLC had the c.823C>T (p.Arg275Trp) mutation. WES was performed for affected individuals III-1, III-4, and IV-18. Subject IV-12 (symbol with vertical black bar in the center) had leukemia. Three individuals (IV-7, IV-9, and V-1 [half-black symbols]) were affected by SCLC. Six unaffected individuals (age at exam ranging from 30 to 55 years) had the c.823C>T (p.Arg275Trp) mutation, and 19 unaffected (age at exam ranging from 26 to 75 years) had wild-type alleles at this locus. In family B, two NSCLC-affected individuals (III-6 and III-7) had the c.823C>T (p.Arg275Trp) mutation. Three unaffected individuals (age at exam ranging from 25 to 49 years) had this mutation, and 13 unaffected (age at exam ranging from 30 to 69 years) had wild-type alleles at this locus. Individual III-4 (symbol with an inner black circle) had both lung cancer and melanoma, but her DNA sample was unavailable for genetic testing. In family C, two NSCLC-affected individuals (II-1 and II-3; ages at onset of 57 and 59 years, respectively) had the c.823C>T (p.Arg275Trp) mutation. Individual I-1 (symbol with an inner black circle) had both lung cancer and prostate cancer, and I-2 (symbol with an inner black circle) had uterine cancer and potentially had lung cancer (this is unverified, and this individual has been out of contact since 2002). In family D, individual II-2 had the mutation (age at onset was 47 years) and had lung adenocarcinoma. Individual I-2 (symbol with an inner black circle) had both lung adenocarcinoma and leukemia.