Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung

Abstract

Background: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. Methods: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantlymutated driver genes in LUAD pathogenesis. Findings: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. Interpretation: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions.

Identification of a long non‑coding RNA signature for predicting prognosis and biomarkers in lung adenocarcinoma

“…LUAD is a large global health challenge (1,26) and our knowledge of its underlying mechanisms may be improved by preclinical next-generation sequencing bioinformatics technology (27,28). However, despite advances in the diagnosis and treatment of LUAD, the OS time of patients with LUAD remains poor (29).…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…Common chromosomal aberrations had been previously described as early events in AAHs, such as 17p chromosomal arm loss which arises prior to TP53 mutation (205) (see Table 1). The latter chromosomal arm loss was previously described in Barret's esophagus as a potential biomarker of pre-neoplastic lesions that would give rise to esophageal adenocarcinoma (205). Furthermore, not only are such differential field cancerization profiles pertinent to early stage lung cancer patients following surgery and thus may be associated with disease relapse (262), but they have been also shown to segregate airways in smokers with lung cancer from airways in smokers without cancer (263,264).…”

“…Furthermore, not only are such differential field cancerization profiles pertinent to early stage lung cancer patients following surgery and thus may be associated with disease relapse (262), but they have been also shown to segregate airways in smokers with lung cancer from airways in smokers without cancer (263,264). Thus, field effects exemplified here by the AI field, can explain how PMLs arise from the field of cancerization and suggest a key role for the accumulation of particular changes (in this case, chromosomal imbalance-driven genomic instability) and selection early in AAH and NSCLC pathogenesis (205). Whether the field carcinogenesis model affects the immune microenvironment as well-remains an intriguing question worth investigating, with promising avenues for lung cancer immune prevention.…”

“…It has become evident that intact and balanced microbiota, on its own merit, has a positive impact on the health and physiology of the host by influencing a variety of biological functions ranging from behavior, to obesity and cancer (217). Indeed, the microbiome has been dubbed as a "key orchestrator of cancer therapy, " modulating chemotherapy, radiotherapy and immunotherapy ↓ Anti-tumor Th1 (IL12A, GZMB) ↑ Pro-tumorigenic Th2 ↑ Pro-inflammatory cytokines (IL-6, TNF-α) in AAH (190,191) ↓ Anti-tumor Th1 (IL12A) ↑ Pro-tumorigenic Th2 ↑ Immune suppressive mechanisms (IL6, IL10) (191,192) ↑ Immune checkpoints (PD-L2, LAG-3) in Lynch syndrome (193) ↑ Immune checkpoints (CTLA-4, CCR2) (191) ↑ Immune checkpoints (PD-1, CTLA−4, VISTA, LAG−3, TIM-3) (191) ↑ CD4+ and CD8+ TILs (194) ↑ Exhausted CD8+ TILs reactive to neoantigens (195) ↓ Cell-mediated immune response (195) Uncontrolled TLR signaling (196,197) ↑ TLR and inflammatory mediators (NF-κB) ↑ downstream chemokines (IL-6, IL−17) (198) ↓ TLR, ↓ Effector cytokine production (IFN-γ, TNF-α) (199) Progressive infiltration of innate immunosuppressive cells and M2 macrophages and T regs in OPLs (188,200) Immature macrophage-lineage cell infiltration (201) Massive tumor immune cell infiltration (201) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (202) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) Common tumor antigens between cancers and PMLs (203) ↑ Neoantigen expression in due to infiltration of CD4+ and CD8+ T cell as well as ↑ PD-1 (179) ↑ Immunogenic neoantigen load activating anti-tumor T cell response (195) Humoral cell-mediated immune response activated against TAA in gastric premalignant lesions (204) Activation of cell-mediated immune response and recognition of neoepitopes (179) Activation of cell-mediated immune response and recognition of neoepitopes (179) Very few chromosomal mutations (TP53 in Barret's esophagus) …”

“…A prominent spatial gradient of AI was reported with increasing proximity to tumor sites, across multiple tumor-adjacent and distant airway epithelia from earlystage NSCLC patients (209). Genome-wide AI field profiles and their causative chromosomal alterations were also pertinent in atypical adenomatous hyperplasias (AAHs), the earliest known PMLs of LUADs (205). Common chromosomal aberrations had been previously described as early events in AAHs, such as 17p chromosomal arm loss which arises prior to TP53 mutation (205) (see Table 1).…”