NEW YORK (GenomeWeb) – A study appearing online today in the American Journal of Human Genetics suggests that a recurrent mutation in a gene best known for its role in Parkinson's disease may also contribute to inherited lung cancer risk.
Researchers from the Medical College of Wisconsin and elsewhere did exome sequencing on three members of a family frequently afflicted by lung cancer. Within that sequence data, they detected mutations in PARK2, a gene that codes for a ubiquitin ligase enzyme involved in processes ranging from metabolism and stress response to cell growth regulation.
Recessive mutations have been linked to early-onset Parkinson's disease, they noted, though the gene's apparent role in excessive growth suppression suggests that genetic glitches that interfere with its usual functions might dial up cancer risk.
Indeed, when the team did targeted PARK2 sequencing in other individuals with lung cancer, it found the same substitution glitch in other members of the same family and in three unrelated lung cancer-prone families, supporting the gene's potential contribution to familial lung cancer risk.
"These results implicate this specific mutation as a genetic susceptibility factor for lung cancer," the study's senior author Ming You, director of the Medical College of Wisconsin's Cancer Center, said in a statement, "and provide an additional rationale for further investigations of this gene and this mutation for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants."
As part of an effort called the Genetic Epidemiology of Lung Cancer Consortium, or GELCC, You and colleagues used the Illumina HiSeq 2000 to do paired-end exome sequencing on germline DNA samples from three individuals with lung cancer from a multi-generational family with several affected members.
The protein-coding portions of the genomes were nabbed using Agilent's SureSelect Human All Exon kit and sequenced to a mean depth of 149-fold coverage.
After filtering through this data for rare, potentially deleterious variants shared by each of the affected family members, the researchers directed their focus to a suspicious substitution mutation in PARK2.
The mutation turned up in five more non-small cell lung cancer patients from the same family, the team reported. And targeted sequencing on the same PARK2 exon in samples from 111 other individuals with familial lung cancer uncovered three more families carrying the same PARK2 glitch.
Nevertheless, the study's authors noted that additional risk variants are likely at play in at least some individuals, since the analysis picked up PARK2 mutations in some — but not all — of the lung cancer patients tested in one of the families.
Sequencing of the full PARK2 gene in 112 more individuals with familial lung cancer led to four more missense mutations in the gene, for instance, suggesting other PARK2 alterations could contribute to lung cancer risk.
The researchers' follow-up analyses indicated that the original lung cancer-related glitch in PARK2 is extremely rare, but has a relatively strong effect size compared to variants detected in prior genome-wide association studies.
"The effect size of [the PARK2 substitution] on familial lung cancer is larger than the effect sizes of BRCA2 and CHEK2 rare variants on spontaneous lung cancer," You and co-authors concluded.