Citations

Objective To determine the harms of ezetimibe in people who need lipid-lowering treatment. Design Systematic review and meta-analysis. Data sources Randomised controlled trials and cohort studies. Eligibility criteria for selecting studies Studies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation. Results 48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials. Conclusions Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents. Review registration PROSPERO CRD42020187437.

Abstract IgM MGUS and Waldenstrom Macroglobulinemia (WM) represent a disease spectrum with highly dissimilar therapeutic management ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. To shed light on the biology that may account for the clinical differences, we used bone marrow (BM) CD19+/CD138+ sorted cells and matched BM plasma from 32 patients (pts) (7 IgM MGUS, 25 WM) and 5 healthy controls to perform the first comprehensive multiomics approach including whole exome sequencing, RNA seq, proteomics and metabolomics. Applying principal component analysis to gene expression profiling, most of WM pts clustered together, while a small subset of them grouped separately with MGUS pts, suggesting a biologic dichotomy within WM. The healthy controls formed a distinct group from most WM and MGUS. We then applied a non-negative matrix factorization consensus clustering to the gene expression data and identified three robust clusters. Cluster 1 (C1) included only WM pts, cluster 2 (C2) included both WM and MGUS pts, and cluster 3 (C3) included all controls as well as a small number of WM and MGUS pts. When mutations commonly identified in WM were analyzed, there was no difference among the three groups (excluding controls) in mutation burden of MYD88 L265P and CXCR4. Interestingly, aberrant expression of TNFAIP3 seemed a distinct feature of C1 as deletion of 6q (which encodes for TNFAIP3) and TNFAIP3 mutations were each significantly enriched in C1 (47%) compared to C2 (0%) and C3 (20%; p=0.04). Individual clusters associated with specific transcriptional signature and clinical features. While C1 displayed enrichment of cell growth, downregulation of inflammatory pathways (eg IL6 and IL8 signaling) and aggressive behavior, C2 showed increased inflammatory signaling and cell survival with indolent behavior. C3 had an intermediate feature with combined proliferative and inflammatory signatures. In accordance with the transcriptomic data, the hallmark of C1 was upregulation of proliferation-associated proteins (eg AKT, MAPK) and downregulation of inflammatory proteins (eg IL4, IL10) while the opposite was observed in C2. Once more, C3 confirmed intermediate features with combined upregulation of proliferation and inflammatory proteins. The metabolism was rewired towards fatty acid catabolism in C1, glycolysis in C2 and anabolism in C3. Accordingly, C1 showed undetectable concentration of 3-hydroxybutyric acid as opposed to C2 which had increased levels of malic and lactic acids, as end products of fatty acid oxidation and glycolysis respectively. Those metabolites had intermediate levels in C3. In conclusion, we identified three molecular clusters with distinct clinical, proteomic and metabolomic features, suggesting a potential biologic classification that may have therapeutic implications. Citation Format: Patrizia Mondello, Jonas Paludo, Joseph Novak, Kerstin Wenzl, Shahrzad Jalali, Jordan Krull, Esteban Braggio, Surendra Dasari, Michelle Manske, Jithma Abeykoon, Asher Chanan-Khan, Robert Kyle, Morie Gertz, Zhi Zhang Yang, Anne Novak, Stephen Ansell. Molecular clusters and functional drivers of IgM monoclonal gammopathies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3487.

Abstract Previous studies have found that the prevalence of subtypes of T cells may be associated with patient outcomes, but a comprehensive analysis of the immune profile in the TM of FL has not been done. In the present study, we identified groups of FL patients with discretely unique TMEs and determined whether the T-cell phenotypes in the TME differed among groups. Using a cohort of 82 FL patients with biopsy specimens collected before treatment, we defined the type of TME based on the content of major lineages (T, B, monocytes/macrophages and NK cells) determined by CyTOF analysis. Hierarchical clustering of this cohort stratified patients into 4 groups with different TME: group 1 (G1) included patients with a high percentage of monocyte/macrophages/NK cells; patients from G2 and G3 were enriched for intratumoral T and B cells, respectively. Patients with intermediate numbers of T and B cells were included in G4. CITRUS analysis revealed that T-cell clusters with phenotypes expressing KLRG1, CD57, PD-1dim and rich in TEMRA cells were significantly more abundant in G1 when compared to G2, G3 or G4. In contrast, T-cell clusters with phenotypes containing CD127, CD45RA, CCR7 or PD-1high cells were significantly less abundant in G1 when compared to other groups. When compared to G3 or G4, 2 classes of T cell clusters, all from CD4+ T cells, were significantly more (CD127+KLRG1-) or less (CD57+PD-1high) abundant in G2, respectively. Clusters with a phenotype rich in short-lived effector cells (SLEC) (from CD8+) were upregulated in G3 when compared to G4. These results suggest that patient groups with distinct TME exhibited variable T-cell phenotypes. To determine the role of T-cell differentiation in predicting patient outcome in FL, we identified T-cell subsets using tSNE plots based on the expression of T-cell maturation markers. We identified 18 subsets (S1-S18) of T cells (11 from CD4, 6 from CD8 and 1 from CD4-CD8-) in each sample. Four subsets - S4 (CD4+TN), S5 (CD4+TCM), S7 (CD8+TN) and S10 (CD8+MEPCs) - were considered to be naïve cells or cells in the early stages of differentiation. Four additional subsets - S8 (CD57+TFH), S9 (CD4+TEXH), S13 (CD8+SLECs) and S17 (CD4+PD-1+Treg) - were memory cells with expression of surface markers indicting late-stage differentiation. We found that the 4 subsets (S4: p=0.08, S5: p=0.01, S7: p=0.04 and S10: p<0.01) with an early-stage phenotype were associated with a favorable clinical outcome. In contrast, subsets (S8: p=0.02, S9: p=0.04, S13: p=0.07 and S17: p=0.06) with a late-stage differentiation phenotype had an unfavorable survival. Supporting this finding, we observed that increased numbers of CD45RA+ T cells correlated with a favorable survival. These results indicate that the differentiation stage may determine the role of T cells in predicting patient outcome in FL. Citation Format: Zhi-Zhang Yang, Hyo Jin Kim, Hongyan Wu, Xinyi Tang, Jordan Krull, Patrizia Mondello, Jose Villasboas, Anne Novak, Stephen Ansell. T-cell phenotype and differentiation vary in the tumor microenvironment of follicular lymphoma and are associated with patient outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2529.

Abstract Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P=<0.0001) and versus F (-90% vs. -80%; P=0.0026). Furthermore sxCCCA rates were significantly higher with A+F than A (53% vs. 25% P = <0.0001) and somewhat higher for F (37%) than A (p=0.068), indicating that superior antiproliferative effects for A+F persist after 6 months on therapy. Lack of Ki67 suppression in response to treatment was observed in the majority of 43 NonLum samples regardless of treatment. Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026.

Abstract Introduction: Radiotherapy has long been examined in association with second malignancies, but the impact of radiotherapy for initial primary lung cancer (IPLC) on the risk of second primary lung cancer (SPLC) remains controversial. We evaluated associations between IPLC radiotherapy and the risks of SPLC and overall mortality among lung cancer survivors. Methods: We identified 689,785 patients diagnosed with IPLC in 1988-2013 from SEER. We applied cause-specific Cox (CSC) regression to evaluate association between IPLC radiotherapy and SPLC risk, adjusting for age at IPLC diagnosis, IPLC stage and histology, and prior history of cancer. To allow a latency period of exposure to IPLC radiotherapy on SPLC risk, we performed subgroup analyses restricted to patients who survived ≥5 and ≥10 years after IPLC diagnosis. Using Cox regression, we evaluated association between IPLC radiotherapy and overall mortality, adjusting for the same covariates used in the CSC analysis. Mediation analysis quantified the indirect effect of IPLC radiotherapy on overall mortality mediated through radiotherapy-driven SPLC diagnosis. Validation utilized data from 7,758 IPLC patients (496 SPLCs) at Mayo Clinic. Results: Of 689,785 IPLC patients, 18,818 (2.7%) developed SPLC in SEER. IPLC patients treated with radiotherapy had a reduced SPLC risk versus non-irradiated patients when evaluated at the time of initial diagnosis (cause-specific hazard ratio [csHR]=0.90, P<1x10-6). However, the association between IPLC radiotherapy and SPLC risk was reversed when analyses were restricted to those who survived at least 5 years (csHR=1.08, P=0.01) and 10 years (csHR=1.16, P=0.009), thus long-term survivors treated with IPLC radiotherapy having a significantly increased risk of SPLC. Mayo Clinic data showed consistent results, with the effect of IPLC radiotherapy increasing from csHR of 2.41 (P<1x10-6) to 3.38 (P=0.001) among 5-year and 10-year survivors, respectively. Similarly, compared to non-irradiated patients, those treated with IPLC radiotherapy showed a significantly increased risk of overall mortality among 10-year survivors (hazard ratio [HR]=1.46, P<1x10-6 in SEER and HR=1.54, P=5.1X10-5 in Mayo Clinic). Mediation analysis showed that a substantial proportion of the total effect of IPLC radiotherapy on overall mortality—ranging from 32% to 59%—was due to radiotherapy-driven SPLC among 10-year survivors in SEER and Mayo Clinic. Conclusions: IPLC radiotherapy is associated with increased risks of SPLC and overall mortality, with its effects more pronounced among long-term survivors. Citation Format: Eunji Choi, Vicky T. Lam, Jacqueline A. Aredo, Ashok V. Kumar, Jason Wampfler, Julie T. Wu, David C. Christiani, Iona Cheng, Christopher I. Amos, Rayjean J. Hung, Leah M. Backhus, Joel W. Neal, Heather A. Wakelee, Ping Yang, Summer S. Han. Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3445.

Abstract Background and Aims: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable attention as a potential anti-cancer strategy, TRAIL agonists have had very limited anti-cancer activity in humans. TRAIL signaling can attenuate the T lymphocyte response. However, this potential immunosuppressive function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, has a dense immunosuppressive microenvironment. Accordingly, CCA provides a model to examine the potential immune regulatory function of TRAIL in cancer biology. Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both Trail and Trail receptor (Tr) were implanted into livers of WT and Tr-/- mice. Hence, in this model the host immune cells express Trail but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr-/- mice had a significant reduction in tumor burden compared to WT mice. Moreover, tumor bearing Tr-/- mice had a significant increase in cytotoxic T lymphocytes (CTLs) and enhanced CTL effector function. Myeloid-derived suppressor cells (MDSCs) were significantly decreased in Tr-/- tumors compared to WT tumors. Furthermore, implantation of SB cells devoid of Trail (SB-Trail-/-) into WT mice resulted in a significant reduction in tumor burden and MDSC infiltration. In vitro functional studies employing SB cells deficient in Tr (SB-Tr-/-) and MDSCs were carried out. There was a significant reduction in proliferation and immunosuppressive function of MDSCs when cocultured with SB-Tr-/- compared to SB cells. These results indicate that TRAIL-TR fosters MDSC growth and immunosuppressive function. In conclusion, we have demonstrated that Tr-/- mice have a significant reduction in CCA tumor burden and MDSC infiltration. Consequently, Tr-/- tumors have enhanced CTL infiltration and function. These data suggest that the TRAIL-TR system mediates tumors immune evasion via MDSCs, and direct targeting of TRAIL on CCA cells is a potential anti-tumor strategy. Citation Format: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera I. Ilyas. Tumor necrosis factor related apoptosis inducing ligand fosters myeloid derived suppressor cell mediated tumor immune evasion in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1315.

Abstract Introduction: Incorporation of mammographic density to breast cancer risk models could improve risk stratification to tailor screening and prevention strategies according to risk. However, robust validation of such models in prospective cohort studies is needed to determine their accuracy in identifying women at different risk levels. Methods: We incorporated Breast Imaging and Reporting Data System (BI-RADS) breast density to a literature-based model with questionnaire-based risk factors and a 313-variant polygenic risk score (PRS). The Individualized Coherent Absolute Risk Estimator (iCARE) tool was used to build and validate a 5-year absolute risk model for breast cancer. The model was evaluated for calibration and discrimination in three prospective cohorts of women of European ancestry (1,468 cases, 19,104 controls): US-based Nurses’ Health Study (NHS I and II) and Mayo Mammography Health Study (MMHS); and Sweden-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Analyses were done separately for women younger (NHS II, KARMA) and older than 50 years (NHS I, MMHS, KARMA). Improvements in risk stratification were assessed among US non-Hispanic White women aged 50-70 years. Results: For women younger than 50 years, the model with questionnaire-based risk factors, PRS and BI-RADS was well calibrated across risk deciles in NHS II, but overestimated risk at the highest risk decile in KARMA. For women 50 years or older, the model showed good calibration in all studies, with evidence of slight overestimation at the highest risk decile and underestimation at the lowest risk decile. The model with PRS and BI-RADS was well calibrated for women at high-risk in both age groups. Incorporation of BI-RADS to questionnaire-based risk factors and PRS improved risk discrimination: area under the curves (AUC) 67.0% (95% CI: 63.5-70.6%) vs. 65.6% (95% CI: 61.9-69.3%) for models with and without BI-RADS for younger women and 66.1% (95% CI 64.4-67.8%) vs. 65.5% (95% CI: 63.8-67.2%) for older women. The model with BI-RADS identified 18.4% population of non-Hispanic US women 50-70 years old above 3% 5-year risk (used for recommending risk-reducing medication in the US), with 42.4% of future cases expected to occur in this group. Addition of BI-RADS led to the reclassification of ~8.0% of US non-Hispanic White women aged 50-70 years at the high-risk threshold (3% 5-year risk), resulting in identification of 4.2% of additional future cases. Conclusion: Integrating BI-RADS with questionnaire-based risk factors and PRS resulted in improved risk stratification among women of European ancestry, with evidence of slight overestimation of risk for women at elevated risk. Additional validation of the integrated model in diverse populations is needed prior to considering clinical applications. Citation Format: Charlotta V. Mulder, Yon Ho Jee, Xin Yang, Christopher G. Scott, Chi Gao, Amber N. Hurson, Mikael Eriksson, Per Hall, Peter Kraft, Celine M. Vachon, Antonis C. Antoniou, Gretchen Gierach, Montserrat Garcia-Closas, Parichoy Pal Choudhury. Validation of an integrated breast cancer risk model with mammographic density in three prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2256.

Abstract Lung cancer (LC) is the most common cause of cancer mortality and the third most common cancer by incidence in the United States. While environmental factors play an important role in its development, LC risk also exhibits a high degree of heritability. Linkage analyses and genome-wide association studies have identified multiple loci associated with increased LC risk; however, much of the heritability has yet to be explained by these loci. Structural mutations, including copy number variations (CNVs), contribute to phenotypic diversity through dosage and/or cis-regulatory effects. Unbiased CNV mapping is only possible with the use of high-depth, short-read sequencing and remains much more complicated and prone to false positives than SNP detection. As the tools necessary for CNV detection have improved, both somatic and germline CNVs have been shown to play an important role in disease, especially cancer, and often they account for a significant proportion of pathogenic variants. Little has been done to understand the role of germline CNVs in the biological pathways of hereditary lung cancer (HLC). The goal of the current project is to utilize the whole exome sequencing (WES) data in identifying the CNVs in the HLC families (≥3 LC/family) recruited by the Genetic Epidemiology of Lung Cancer Consortium (GELCC). This work uses germline WES data from 203 individuals (60 with a LC diagnosis) from 25 HLC families (≥3 LC affected/family). We limited our investigation to CNVs called by two independent tools using read depth to infer copy number changes and genomic breakpoints: GATK 4 (https://gatk.broadinstitute.org) and XHMM (https://atgu.mgh.harvard.edu/xhmm/). We have identified CNVs (deletions) in the following protein coding genes: KIR2DL1 (19q13.42; OR=1.77), DMBT1 (10q26.13; OR=1.56), SIBPB1 (20p13; OR=1.53), LILRA6 (20p13; OR=1.53), and HLA-DRB5 (6p21.32; OR=1.64) in ≥3 families in at least two individuals/family. All of these genes with the exception of HLA-DRB5 were previously reported in LC studies; HLA-DRB5 was reported in other cancer studies. DMBT1 was reported to be a candidate tumor suppressor gene and frequent loss of heterozygosity (LOH) was observed in several human tumors. It is highly expressed in lung and loss of expression was reported in LC cell lines. All CNVs identified in our study are consistent with Mendelian expectations and appear to be uncommon in the general population. CNVs in these genes may contribute to the lung cancer risk in the HLC families. Further validation of the identified variants is ongoing. We will consider overall CNV burden and disease association with identified deletions and duplications. The enrichment of rare variants in oncogenically associated genes that co-segregate with LC provides specific mutations for future work and improves our understanding of the inheritance and pathogenesis of LC. Citation Format: John Waldron, Kirsten W. Termine, Anthony M. Musolf, Mariza de Andrade, Colette Gaba, Ramaswamy Govindan, Ping Yang, Ming You, Ellen Jaeger, Angelle F. Bencaz, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson, Diptasri M. Mandal. Analyses of whole exome sequencing (WES) data of hereditary lung cancer families identify germline copy number variations (CNVs) in multiple genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1452.

Abstract A 39-year-old man presented with progressive dyspnea and lower extremity edema. Doppler ultrasound demonstrated bilateral leg partially occluded venous thromboses. A V/Q scan revealed a mismatched perfusion defect involving the entire right middle and lower lobes. Subsequent CT pulmonary angiogram revealed a mass lesion occluding the right interlobar pulmonary artery. Endobronchial ultrasound–guided fine-needle aspiration of the mass was concerning for neoplasm. 18 F-FDG PET/CT demonstrated marked hypermetabolism of the mass lesion. Patient underwent transmediastinal right pneumonectomy with histopathologic diagnosis of pulmonary artery angiomatoid fibrous histiocytoma, a rare etiology mimicking large pulmonary artery embolism.

Abstract Background Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants ( p ≤ 5 × 10 −5 ) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 ( VCAM1 / EXTL2 ) (discovery: odds ratio (OR T allele ) = 0.82, p = 9.05 × 10 −6 and replication: OR T allele = 0.89, p = 5.35 × 10 −3 ) and rs943126 from pantothenate kinase 1 ( PANK1 ) (discovery: OR C allele = 0.85, p = 3.10 × 10 −5 and replication: OR C allele = 0.89, p = 1.30 × 10 −2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.