2302 - Characterization through whole exome sequencing of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small lung cancer (NSCLC)

Background

Individual susceptibility to carcinogens may depend on the genetic background. We sequenced the constitutional exome of individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco-induced NSCLC. We hypothesized that such selection would enrich the frequencies of the alleles that contribute to the trait.

Methods

From an identification cohort (n = 3,631) we selected 100 caucasian heavy smokers that either developed NSCLC -specifically adenocarcinoma- at an early age (cancer-cohort, n = 50) or that did not present NSCLC or any other tumors at an advanced age (cancer-free cohort, n = 50). We sequenced their germline DNA using the Agilent Human Exome Capture v5, which includes 21,522 genes (357,999 exons). We selected genetic variants located in the exonic regions and splice sites of the genes evaluated; that codified for non-synonymous codons; and that showed allelic differences >15% between both cohorts.

Results

The mean age for the cancer and cancer-free cohorts was 50 (range 34-55) and 78 years (72-90). Mean tobacco consumption was 44 (range 6-72) and 55 pack-years (20-124). Median exome sequencing coverage was 96% at > 10X and median depth was 97X. We identified 229 differential variants between both cohorts, located in 189 genes. The most significant variants (p < 10^-4) are shown in the table. Twenty genes or family genes included >3 differential genetic variants (range 3-25): ADAMTS, ALPK2/3, ankyrins, APOL4, CCDC, CRIPAK, FYCO1, HLA-A, keratins, mucins, olfactory receptors, PDPR, PRAME family, RFPL2, RP1L1, SAMD9, SLC transporters, anoctamins, TTN, and ZNF family.

Conclusions

We identified genetic variants associated with individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced NSCLC. These variants warrant further study to characterize their impact in the development of these extreme phenotypes.

Clinical trial identification

Legal entity responsible for the study

Universidad de Navarra.

Funding

Spanish Society of Medical Oncology, Fundación SEOM and Fundación Salud 2000, Government of Navarra.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.Table: 1837PD