Abstract 2919: Homologous recombination deficiency in non-small cell lung cancer: genetic and epigenetic causes beyond HRR

Abstract Introduction: The mechanisms of homologous recombination deficiency (HRD) in non-small cell lung cancer (NSCLC) remain understudied, mainly due to the low prevalence of germline or somatic mutations in relevant genes such as BRAC1/2 in this cancer type. However, recent reports suggest that an important subset of patients present high genomic scarring score (GSS), indicating HRD, although the causes are not always clear. In this work, we examined a cohort of 147 patients and sought to correlate GSS, mutational profile and relevant gene expression with response to PARP inhibition in preclinical functional experiments. Experimental Procedures: We used next generation sequencing to evaluate the GSS of each primary tumor with a commercially available sequencing kit which also provides information on the genetic status of relevant HRR and other genes. We performed rt-PCR analyses to assess the expression of certain genes, and we established patient-derived xenografts to examine the response of high and low GSS (h-GSS and l-GSS respectively) tumors to PARP inhibition. Results: 42 out of 147 tumors (28.6%) presented a GSS>50 (h-GSS). The prevalence of germline or somatic mutations in HRR genes was not significantly different between h-GSS and l-GSS tumors (18/42 vs 37/105, p=0.388). On the contrary, TP53 mutation frequency (p<0.001) as well as variant allele frequency (p<0.0001) correlated significantly with GSS. Expression of HRR genes was marginally higher in h-GSS tumors, whereas expression of the epigenetic factor KMT2C was significantly lower in that subset and presented an inverse correlation with both GSS (p=0.0059) and TP53 variant allele frequency (p=0.02). The growth of h-GSS PDXs was significantly hampered upon PARP inhibition. Conclusions: Our data show that for early-stage NSCLC, the GSS might be a valuable biomarker to stratify patients who might benefit from PARP inhibition. As this is not dependent on HRR genetic status in this cohort, further experimentation is needed to elucidate the complex relationship between TP53 status, KMT2C expression and HRD. Citation Format: Katerina Tsilingiri, Anna Chalari, Georgia Christopoulou, Alexandra Voutsina, Pantelis Constantoulakis, Konstantinos Potaris, Ioannis Vamvakaris, Dora Hatzidaki, Georgina Zachou, Giannis Vatsellas, Vassilis Georgoulias, Athanasios Kotsakis, Apostolos Klinakis. Homologous recombination deficiency in non-small cell lung cancer: genetic and epigenetic causes beyond HRR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2919.