Brown, Kevin M.

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Patients with systemic sclerosis are at high risk of developing systemic sclerosis–associated interstitial lung disease. Symptoms and outcomes of systemic sclerosis–associated interstitial lung disease range from subclinical lung involvement to respiratory failure and death. Early and accurate diagnosis of systemic sclerosis–associated interstitial lung disease is therefore important to enable appropriate intervention. The most sensitive and specific way to diagnose systemic sclerosis–associated interstitial lung disease is by high-resolution computed tomography, and experts recommend that high-resolution computed tomography should be performed in all patients with systemic sclerosis at the time of initial diagnosis. In addition to being an important screening and diagnostic tool, high-resolution computed tomography can be used to evaluate disease extent in systemic sclerosis–associated interstitial lung disease and may be helpful in assessing prognosis in some patients. Currently, there is no consensus with regards to frequency and scanning intervals in patients at risk of interstitial lung disease development and/or progression. However, expert guidance does suggest that frequency of screening using high-resolution computed tomography should be guided by risk of developing interstitial lung disease. Most experienced clinicians would not repeat high-resolution computed tomography more than once a year or every other year for the first few years unless symptoms arose. Several computed tomography techniques have been developed in recent years that are suitable for regular monitoring, including low-radiation protocols, which, together with other technologies, such as lung ultrasound and magnetic resonance imaging, may further assist in the evaluation and monitoring of patients with systemic sclerosis–associated interstitial lung disease. A video abstract to accompany this article is available at: https://www.globalmedcomms.com/respiratory/Khanna/HRCTinSScILD

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Abstract Genome wide association studies (GWAS) have mapped multiple independent cancer risk loci (n = 6) to a small region on chr5p15.33 for at least ten distinct cancers, including bladder, breast, glioma, lung, melanoma, non-melanoma skin, ovarian, pancreas, prostate, and testicular germ cell cancer. This region harbors two plausible target genes, TERT which encodes the catalytic subunit of telomerase reverse transcriptase which maintains chromosome ends by adding telomeres repeats, and CLPTM1L which encodes the cleft lip and palate transmembrane protein 1-like protein which promotes cancer cell growth, protect cells from apoptosis, and can induce abnormal cytokinesis. The most significant pancreatic cancer GWAS SNP on chr5p15.33 was rs401681 (P = 3.7×10−7, OR = 1.19), located in the 13th intron of the CLPTM1L gene and within the independent multi-cancer risk locus in this region most distant from TERT. Imputation and fine mapping in pancreatic cancer resolved this signal by three orders of magnitude (P = 1.4×10−10, OR = 1.30) to a set of seven highly correlated SNPs. Electrophoretic mobility shift assays (EMSA) and luciferase assays across these SNPs led us to a single SNP, rs36115365, that showed allele-specific effects in both assays and overlapped with prominent ENCODE marks indicating regulatory potential. Examining this SNP across cell lines derived from multiple types of cancer linked to this locus, specifically pancreatic, testicular, lung, and melanoma, established a consistent pattern of a specific protein binding and enhanced regulatory activity for the risk allele across eight cancer cell lines (two cell lines per cancer type). siRNA-based targeting of the putative gene regulatory-region harboring rs36115365 resulted in a strong inhibition of TERT expression (average 60%, range 45-85%) but no effect on CLPTM1L expression. This inhibition of TERT expression was stronger from the pancreatic cancer risk as compared to the protective allele. Quantitative mass spectrometry identified Zinc finger protein 148 (ZNF148) as the protein specifically binding the risk allele, further supported by direct and allele-specific binding of purified recombinant ZNF148 in EMSA assays. Lastly, siRNA-mediated knockdown of ZNF148 resulted in significant reduction of TERT but not CLPTM1L expression across multiple cancer cell lines. Our results indicate that the pancreatic cancer GWAS signal at the single independent chr5p15.33 multi-cancer risk locus most distant from TERT may be explained by a single SNP that influences TERT expression via ZNF148. Citation Format: Kevin M. Brown, Jun Fang, Jinping Jia, Zhaoming Wang, Matthew Makowski, Tongwu Zhang, Jason Hoskins, Jiyeon Choi, Younghun Han, Mingfeng Zhang, Mai Xu, Peter Kanetsky, Andresson Thorkell, Gloria M. Petersen, Katherine L. Nathanson, Christopher I. Amos, Maria T. Landi, Stephen J. Chanock, Michiel Vermeulen, Laufey T. Amundadottir. Functional characterization of a multicancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4610. doi:10.1158/1538-7445.AM2015-4610

Abstract It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not “alveolitis” but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Abstract Rationale An efficacious medical therapy for idiopathic pulmonary fibrosis (IPF) remains elusive. Objectives To explore the efficacy and safety of etanercept in the treatment of IPF. Methods This was a randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically progressive IPF. Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin (DlCOHb) and change in the alveolar to arterial oxygen pressure difference P(a–a)O2 at rest from baseline over 48 weeks. Measurements and Main Results Eighty-eight subjects received subcutaneous etanercept (25 mg) or placebo twice weekly as their sole treatment for IPF. No differences in baseline demographics and disease status were detected between treatment groups; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9% of predicted. At 48 weeks, no significant differences in efficacy endpoints were observed between the groups. A nonsignificant reduction in disease progression was seen in several physiologic, functional, and quality-of-life endpoints among subjects receiving etanercept. There was no difference in adverse events between treatment groups. Conclusions In this exploratory study in patients with clinically progressive IPF, etanercept was well tolerated. Although there were no differences in the predefined endpoints, a decreased rate of disease progression was observed on several measures. Further evaluation of TNF antagonists in the treatment of IPF may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 00063869).