Abstract
BackgroundMicropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.MethodsWe performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.ResultsTumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.ConclusionWe identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.
Highlights
Lung adenocarcinoma (LADC) is the most prevalent histologic type of non-small cell lung cancer (NSCLC), accounting for nearly 50% of all diagnosed cases worldwide [1]
Of the 49 LADC tumor samples within the discovery cohort, 21 tumors had a high percentage of micropapillary component (MPC) (30–100%), 27 tumors contained a low percentage of MPC (0 to 20%), and one tumor does not have detectable MPC
By analyzing the mutation frequency using the same ranked groups as above, we found that mutations in brain-specific angiogenesis inhibitor 3 (BAI3), AT-rich interactive domain-containing protein 2 (ARID2), cytochrome P450 2D6 (CYP2D6), and mammalian target of rapamycin (MTOR) had the trend to correlate with higher MPC percentage/similarity (Supplementary Table 8; Jonckheere’s trend test)
Summary
Lung adenocarcinoma (LADC) is the most prevalent histologic type of non-small cell lung cancer (NSCLC), accounting for nearly 50% of all diagnosed cases worldwide [1]. Previous studies have revealed that tumors with MPC have a higher incidence of oncogenic mutations, such as EGFR, KRAS, and BRAF, compared with other histological subtypes [5, 6]. The frequency of these oncogenic mutations was associated with the percentage of MPC in the entire tumor, controversial results have been observed [7, 8]. Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments
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