Germline mutations of Holliday junction resolvase genes in multiple primary malignancies involving lung cancer lead to PARP inhibitor sensitization.

BACKGROUND

The incidence of multiple primary malignancies (MPMs) involving lung cancer has increased in recent decades. There is an urgent need to clarify the genetic profile of such patients and explore more efficacious therapy for them.

METHODS

Peripheral blood samples from MPMs involving lung cancer patients were assessed by whole exome sequencing (WES) and the identified variants were referenced for pathogenicity using the public available database.Pathway enrichment analysis of mutated genes was performed to identify the most relevant pathway. Then the effects of mutations in relevant pathway on function and response to targeted drugs were verified by in vitro and in vivo experiments.

RESULTS

Germline exomes of 71 patients diagnosed with MPMs involving lung cancer were sequenced. Pathway enrichment analysis shows that homologous recombination repair (HRR) pathway has the strongest correlation. Moreover, HRR genes, especially key Holliday junction resolvases (HJR) genes (GEN1, BLM, SXL4, and RMI1), were most frequently mutated, unlike the status in the samples from patients with lung cancer only. Next, we identified a total of 7 mutations in HJR genes led to homologous recombination DNA repair deficiency and rendered lung cancer cells sensitive to poly ADP-ribose polymerase (PARP) inhibitor treatment, both in vitro and vivo.

CONCLUSIONS

This is the first study to map the profile of germline mutations in patients with MPMs involving lung cancer. This study may shed light on early prevention and novel targeted therapies for MPMs involving lung cancer patients with HJR mutations.