Abstract
BackgroundThere were scarcely germline variants of familial lung cancer (LC) identified. We conducted an study with whole-exome sequencing of pedigrees with familial lung cancer to analyze the potential genetic susceptibility.MethodsProbands with the highest hereditary background were identified by our large-scale epidemiological study and five ones were enrolled as a learning set. The germline SNPs (single-nucleotide polymorphisms) of other five similar probands, four healthy individuals in the formerly pedigrees and three patients with sporadic LC were used as a validation set, controlled by three healthy individuals without family history of any cancer. The network of mutated genes was generated using STRING-DB and visualized using Cytoscape.ResultsSpecific and shared somatic mutations and germline SNPs were not the shared cause of familial lung cancer. However, individual germline SNPs showed distinct protein-protein interaction network patterns in probands versus healthy individuals and patients with sporadic lung cancer. SNP-containing genes were enriched in the PI3K/AKT pathway. These results were validated in the validation set. Furthermore, patients with familial lung cancer were distinguished by many germline variations in the PI3K/AKT pathway by a simple SVM classification method. It is worth emphasizing that one person with many germline variations in the PI3K/AKT pathway developed lung cancer during follow-up.ConclusionsThe phenomenon that the enrichments of germline SNPs in the PI3K/AKT pathway might be a major predictor of familial susceptibility to lung cancer.
Highlights
There were scarcely germline variants of familial lung cancer (LC) identified
We found that the subgroup with a family history of at least two first-degree relatives affected by LC was at highest risk
While comparing patients of adenocarcinoma with squamous carcinoma, a family history of disease in first-degree relatives significantly increased the risk of lung adenocarcinoma (OR = 2.74, P = 0.018)
Summary
There were scarcely germline variants of familial lung cancer (LC) identified. Previous studies have identified very few germline variants associated with familial lung cancer. An increased familial risk of LC observed in our previous study provided indirect evidence that genetic factors contribute to susceptibility to LC [1]. This echoed an early observation that the LC exhibited familial aggregation. One explanation for the mutational heterogeneity observed in cancer is the fact that genes act together in various signaling and regulatory pathways and protein complexes [3]. In one study using next-generation sequencing, disruptive germline mutation genes were identified between familial and sporadic LC [12]. The independent statistical analysis of each genomic nucleotide position in GWAS (Genome-wide association studies) makes it difficult to assess the complex interactions among many genes containing these SNPs
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