2004P Exome sequencing of germ-line DNA from young-onset and/or ALK-fusion-positive lung cancer patients

A small subset of lung carcinomas (LCs) occur in non-smokers, with some patients developing the malignancy in an unusually young age. This mode of disease appearance is particularly characteristic for ALK-driven LCs. We hypothesized that young-onset and/or ALK-fusion-positive LC may be associated with a germ-line genetic defect. We expected that if a potential causative allele will be detected, its significance could be validated in an extended genotyping study due to existence of founder effect in Russian population. The study included 19 LC patients [14 fusion-positive LCs (age range: 24-71 years; 6/14 (43%) subjects aged < 45 years); 3 young-onset (< 40 years) LCs with negative or unknown fusion status; 2 women with multiple primary tumors (bilateral LC, 47 years and LC + cervical cancer, 43 years)]. Blood DNA was subjected to exome sequencing. Data analysis considered truncating heterozygous mutations and potentially pathogenic biallelic missense mutations in genes with known role in cancer pathogenesis. There were single instances of ATM p. Q1478X, BARD1 c. 2300_2301del, CHEK2 c.1046dupA, XPA c.268_269insA and XRCC2 c.96delT heterozygous mutations. The analysis of consecutive LC cases (n = 420-456), ALK-fusion positive LCs (n = 95-166) and young-onset LC patients (n = 80-173) did not reveal additional instances of these alleles. In addition, we considered for further study biallelic c.C883T (p.T278I) mutation in the NEIL1 gene, which was detected in one patient and was very likely to affect the function of the protein. Case-control study involving 554 LC patients and 250 healthy controls revealed equal frequency (3.2%) of NEIL1 c.C883T heterozygotes in both groups, while no new instances of homozygous genotype was identified. Although young-onset and/or ALK-fusion-positive LCs constitute an especial category of LC, this exome sequencing study failed to identify germ-line predisposing factors for this disease.