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Purpose: Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that in females the proportion of lung cancer cases that is unrelated to tobacco smoking reaches fifty percent, making questionable the etiology of the disease., Materials and Methods: A never-smoker female with primary EGFR/KRAS/ALK-negative squamous cell carcinoma of the lung and their normal sibswere subjected to a novel integrative "omic" approach using a pedigree-based model for discovering genetic factors leading to cancer in the absence of well-known environmental trigger. A first-stepwhole-exome sequencing on tumor and normal tissue did not identify mutations in known driver genes. Building on the idea of a germline oligogenic origin of lung cancer, we performed whole-exome sequencing of DNA from patients' peripheral blood and their unaffected sibs. Finally, RNA-sequencing analysis in tumoral and matched non-tumoral tissues was carried out in order to investigate the clonal profile and the pathogenic role of the identified variants., Results: Filtering for rare variants with Combined Annotation Dependent Depletion (CADD) > 25 and potentially damaging effect, we identified rare/private germline deleterious variants in 11 cancer-associated genes, none ofwhich, except one, sharedwith the healthy sib, pinpointing to a "private" oligogenic germline signature. Noteworthy, among these, two mutated genes, namely ACACA and DEPTOR , turned to be potential targets for therapy because related to known drivers, such as BRCA1 and EGFR ., Conclusion: In the era of precision medicine, this report emphasizes the importance of an "omic" approach to uncover oligogenic germline signature underlying cancer development and to identify suitable therapeutic targets as well.