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Genetic Alterations in Preinvasive Lung Synchronous Lesions.

ABSTRACT: PURPOSE:Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD). Materials and Methods:We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing. RESULTS:Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions. CONCLUSION:Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

SUBMITTER: Ahn S

PROVIDER: S-EPMC7577825 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Genetic Alterations in Preinvasive Lung Synchronous Lesions.

Ahn Soyeon S Lim Jisun J Park Soo Young SY Kim Hyojin H Kwon Hyun Jung HJ Han Yeon Bi YB Lee Choon-Taek CT Cho Sukki S Chung Jin-Haeng JH

Cancer research and treatment 20200605 4

<h4>Purpose</h4>Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD).<h4>Materials and methods</h4>We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three pati ...[more]

PMID: 32599981

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Project description:BackgroundAfrican Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease.MethodsWe selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch.ResultsWe observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001).ConclusionsOverall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

Project description:BACKGROUND:Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation. OBJECTIVE:We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation. METHODS:We performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding). RESULTS:All 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific TH2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation. CONCLUSION:Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific TH2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism.

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Genetic Alterations in Preinvasive Lung Synchronous Lesions.

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Genetic Alterations in Preinvasive Lung Synchronous Lesions.

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