Abstract 771: Mechanisms of genetic predisposition to multifocal lung cancer

Abstract Detection of multiple primary lung cancers is increasing in frequency, with up to 15% of all non-small cell lung cancer (NSCLC) patients presenting with two or more anatomically separate tumor nodules on CT scans. Increased detection is in part due to expanded lung cancer screening criteria in an aging population. Distinguishing multiple primary tumors from intrapulmonary metastases can be challenging, yet is critical for determining clinical management. Current models predict development of multiple primary tumors out of a cancerized field, such as occurs due to smoking. The occurrence of multiple primary tumors is unexplained in patients with EGFR-mutant lung cancer (~15% of all NSCLC), lacking environmental exposures. We identified patients with non-small cell lung cancer (NSCLC) who presented with multiple primary EGFR-mutant tumors, in the absence of family history of lung cancer or heavy smoking. We subjected the macrodissected tumors and surrounding normal tissues to whole exome sequencing as well as to analysis of hypermutable poly-guanine (poly-G) repeats, which are two orthogonal methods of lineage tracing. An additional familial case with a germline EGFR-T790M mutation was used to establish parameters for timing of somatic mutations, and functional properties of novel germline variants were modeled in vitro. Of eleven non-familial NSCLC cases with two or more geographically distinct EGFR-mutant lung cancers, two patients harbored a germline EGFR variant allele, which confers moderately enhanced signaling in vitro, followed by a somatically acquired EGFR mutation. In an additional four cases, both whole exome sequencing and poly-G repeat analyses indicate a distant shared somatic cell-of-origin, consistent with embryonic mosaicism. Three cases revealed clinically unappreciated metastasis and two cases remain unexplained. Together, our data suggest that multiple primary lung cancers with somatic EGFR driver mutations may result from genetic susceptibility, attributable either to attenuated EGFR germline variants or to embryonic mosaicism resulting in geographically disparate patches of predisposed lung tissue. Such predisposed cases should be surveilled for early detection of future tumors, and surgical resection in these cases should consider the life-long risk of additional cancers. Citation Format: Risa Burr, Ignaty Leshchiner, Christina L. Costantino, Martin Blohmer, Tilak Sundaresan, Justin Cha, Karsen Seeger, Sara Guay, Brian P. Danysh, Ira Gore, Raquel A. Jacobs, Kara Slowik, Filippo Utro, Kahn Rhrissorrakrai, Chaya Levovitz, Jaimie L. Barth, Taronish Dubash, Brian Chirn, Laxmi Parida, Lecia V. Sequist, Mari Mino-Kenudson, Kamila Naxerova, Shyamala Maheswaran, Gad Getz, Daniel A. Haber. Mechanisms of genetic predisposition to multifocal lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 771.