237P Genomic profiling of aggressive pathologic features in lung adenocarcinoma

The presence of lympho-vascular invasion (LVI), spread through air spaces (STAS) and Grade 3 pattern (from the International Association for the Study of Lung Cancer grading system) have been related to aggressive phenotype and worse prognosis in patients with lung adenocarcinoma, but the associations and differences in genomics of these pathologic features are largely uncharacterized. A total of 1306 next-generation sequencing (NGS) samples of adenocarcinoma, evaluated for at least one of the pathological features, were included in the analysis of genomic mapping. The dataset of East Asian ancestry from OncoSG was used for Tumor-Node-Metastasis-Biomarker (TNMB) classification and prognostic assessment. LVI, STAS, Grade 3 were present in 63 (4.8%), 214 (16.4%), 185 (14.2%) samples, respectively. In LVI, 6 enriched mutations were identified. TP53 (60% versus 31%, P<0.001) was the most significantly enriched mutation. In STAS, 18 enriched mutations were identified. TP53 (52% versus 28%, P<0.001) and PTEN (6% versus 1%, P<0.001) were more pronounced. Similarly, 20 enriched mutations were identified in Grade 3. TP53 (58% versus 32%, P<0.001), LRP1B (13% versus 5%, P<0.001), KRAS (17% versus 8%, P<0.001), NF1 (10% versus 3%, P<0.001) were more pronounced. EGFR was the only significantly enriched mutation in STAS-negative and moderate-grade samples. TP53 and NF1 were significantly enriched in all three pathological characteristics. However, CHEK2 and RB1 were specific to LVI with significance, and CTNNB1, HGF, EPHA3, RET were specific to STAS with significance. Similarly, KRAS, POLE, NTRK3, IDH1, STK11 were significantly specific to Grade 3. The combination of STK11, PTEN, and TOP2A selected from the above could be a new indicator of TNMB classification for prognostic prediction, HR for stage II versus I of TNMB was 2.28 (95% CI 1.36-3.86, P<0.001), for stage III versus II was 1.95 (95% CI 1.04-3.21, P=0.031). This study suggests that LVI, STAS and Grade 3 pattern harbor distinct genomic profiles compared to samples without among features, highlighting the common and unique characteristics of these aggressive features. Exclusive mutations as biomarkers are expected to improve customary staging.