Candidate mutations for early-onset lung cancer by family genome sequencing

Early-onset lung cancer has been studied as a rare, but distinct, sub-type of lung cancer. Genome-wide association studies (GWAS) have linked several genes with this form of malignancy. We sequenced the genomes of a family quartet in which one of the offspring was diagnosed with early-onset lung cancer at about 48 years of age. The family has a history of heavy smoking and the father had in the past been diagnosed with head and neck cancer. The DNA source was blood, which leads us to concentrate our analysis on Mendelian inheritance models. To make the inheritance pattern explicit, we establish the parental origin of the offspring’s genomes through phasing of their chromosomes. This helps identify whether mutations in the proband came from the father or the mother. More than 18 million sequence variants were initially identified in the proband through comparison to the hg19 reference genome. We reduce this list to fewer than 200 potentially functional variants (e.g. single nucleotide variations and short indels) present in the genomes of the proband and at least one parent, by applying a series of filters. We refine the list of candidate mutations further by comparison to gene candidates from GWAS studies and genes that are mutated in lung cancer tissue as recorded by The Cancer Genome Atlas. The results of our analysis are discussed and conclusions about possible causative mutations for early-onset lung cancer are drawn.