Abstract Understanding the cascade of molecular events leading to metastatic progression of lung squamous cell carcinomas (LSCC) is critical to intervene with appropriate treatment options. In this era of precision medicine, identification of key genetic alterations through cutting edge technologies such as high-resolution single nucleotide polymorphism arrays and next generation sequencing have revolutionized cancer therapeutics and surveillance impacting overall survival. The present study investigated resected primary cancer tissues and matched bronchoscopically abnormal follow up mucosal biopsies from 4 LSCC patients with an aim to characterize clonal molecular genetic changes therein. A total of 25 samples including matched normal lymph node as control from these subjects were analyzed on Affymetrix high-resolution 250K SNP array (NspI) platform. Copy number loss and copy neutral loss (LOH) and genomic amplifications were measured in these samples and clonal molecular alterations were also assessed. We observed clonal copy number and copy neutral loss in various potential tumor suppressor genes (TSGs) including GPC5, LTBP1, SOX6, IRF2, LRP8, GSTT1, DAPK1, CACNA1C, DNAH8, CDKAL1, PPP2R2B, CDH4, MAL1D1, PTPRT, NRG2 and FMNL2. Notably, homozygous deletion was observed in one patient in 10q11.1-10q11.22 chromosomal region. The genes effected due to homozygous deletion includes: MARCH8, ANUBL1, FAM21C, CTGLF1, PTPN20A, PTPN20A, PTPN20B, FRMPD2L1, FRMPD2L2, SYP15, GPRIN2, PPYR1 and ANXA8. Clonal amplification (3-10 fold) of molecules that primarily function in mitochondria was also noted in primary cancer and corresponding mucosal biopsies of the majority of these subjects. This includes SUPV3L1, PDK2, MDH1, VDAC2, LONP1, NDUFA11, and OGG1, key molecules, which regulate normal mitochondrial function and homeostasis. Thus, molecular profiling of histologically normal appearing biopsies utilizing high-resolution SNP arrays identified primary cancer associated novel nuclear and mitochondrial genetic alterations in resected lung cancer patients who were heavy smokers. Presence of LSCC associated clonal genetic alterations in the histologically normal appearing mucosal biopsies suggests for possible treatment refractory secondary tumor evolution from the respiratory epithelium harboring the necessary molecular aberrations. Periodic navigation through molecular profiling of the resected LSCC patients and further functional characterization of the identified molecules could lead to the development of new monitoring and treatment strategies. Acknowledgement: Supported by UTHSCT, Willett Foundation and ECSU-NIH-MARC award. Note: This abstract was not presented at the meeting. Citation Format: Julie V. Philley, Kayla Johnston, Hirendra N. Banerjee, David E. Griffith, Santanu Dasgupta. Clonal nuclear and mitochondrial genetic alterations in smoker lung cancer patients and their histologically normal appearing follow-up biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3332.