Philipp Hofer

Objectives: Biobanks collect biological material prospectively for future, yet unspecified research needs. The relationship between collection strategy and actual utilization remains poorly documented, yet understanding usage patterns is critical for resource allocation and planning. We aimed to analyze the time until first use and the utilization rates stratified by collection type and sample material. Methods: We conducted a retrospective analysis of metadata for all submissions (patient sample set per timepoint) deposited in 2019 (n = 13,666 from 56 collections) at the MedUni Wien Biobank. Collections were classified as prospective cohorts (without predefined hypotheses) or dedicated studies. Utilization was assessed at three levels: collections accessed, submissions from which at least one aliquot was requested, and total aliquots distributed. Results: Within 6–7 years, 31/56 collections (55%) were accessed, with 3466/13,666 submissions (25.4%) and 7565 of ~218,000 aliquots (3.5%) utilized. Among accessed collections, 21/35 were prospective cohorts, and 10/21 were dedicated studies. Median submission utilization was 54.2% (Q1–Q3: 25.2–93.1%). Among accessed submissions, conditional median time was 926 days (Q1–Q3: 438–1573). Serum was most frequently requested (24/31 projects). Aliquot requests per submission varied by material: median of 1 aliquot per sample for all materials except for citrate (2) and lithium heparin (5) plasma. Four material types showed no demand: buffy coat, ccfDNA, double-centrifuged citrate plasma, and saliva. Conclusions: The 3.5% aliquot-level utilization rate, numerically below internationally reported 10–20%, reflects metric granularity and the broad aliquoting strategy rather than low sample demand. Material-specific timing and demand patterns provide an evidence base for resource planning in hospital-based biobanks.

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Cornelia Zöchmeister1, *, Stefanie Brezina1, *, Philipp Hofer1, Andreas Baierl2, Michael M. Bergmann3, Thomas Bachleitner-Hofmann3, Judith Karner-Hanusch3, Anton Stift3, Armin Gerger4, Gernot Leeb5, Karl Mach5, Sivaramakrishna Rachakonda6, Rajiv Kumar6 and Andrea Gsur1 1Medical University Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria 2University of Vienna, Department of Statistics and Operations Research, Vienna, Austria 3Medical University Vienna, Department of Surgery, Vienna, Austria 4Medical University of Graz, Division of Oncology, Department of Internal Medicine, Graz, Austria 5Hospital Oberpullendorf, Burgenland, Austria 6German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany *These authors have contributed equally to this work Correspondence to: Andrea Gsur, email: andrea.gsur@meduniwien.ac.at Keywords: telomere length; colorectal cancer; adenoma; cancer epidemiology Received: September 08, 2017 Accepted: January 31, 2018 Published: February 07, 2018 ABSTRACT Considering the high prevalence of colorectal cancer (CRC) and relatively high mortality there is strong interest in identification of clinically relevant biomarkers. Telomere shortening is supposed to contribute to genomic instability and crucially involved in process of carcinogenesis. Peripheral blood leukocyte (PBL) telomere length was previously investigated in several studies as potential biomarker for CRC but with controversial results. This prompted us to investigate relative PBL telomere length in association with different histological findings throughout the continuum of colorectal carcinogenesis in order to reflect the whole spectrum of putative CRC development in a large study involving 2011 individuals. The study based on the Colorectal Cancer Study of Austria (CORSA), including 384 CRC cases as well as age- and gender-matched 544 high-risk adenomas, 537 low-risk adenoma patients and 546 colonoscopy-negative controls. Relative expression of telomeric repeats and the single copy reference gene, albumin (T/S ratio) was determined using monochrome multiplex quantitative PCR (MMQPCR). Telomeres were found to be significantly longer in CRC patients compared to control subjects (P = 3.61x10^-6). Yet, no significant differences in telomere length could be detected for high-risk (P = 0.05956) and low-risk colorectal adenoma patients (P = 0.05224). In addition, results presented in this manuscript highlight the impact of various epidemiological factors on PBL telomere length and its involvement in CRC. However, further large studies also including colorectal adenomas are necessary to confirm these results.

Characterization of the colon cancer immunome and its autoantibody signature from differentially-reactive antigens (DIRAGs) could provide insights into aberrant cellular mechanisms or enriched networks associated with diseases. The purpose of this study was to characterize the antibody profile of plasma samples from 32 colorectal cancer (CRC) patients and 32 controls using proteins isolated from 15,417 human cDNA expression clones on microarrays. 671 unique DIRAGs were identified and 632 were more highly reactive in CRC samples. Bioinformatics analyses reveal that compared to control samples, the immunoproteomic IgG profiling of CRC samples is mainly associated with cell death, survival, and proliferation pathways, especially proteins involved in EIF2 and mTOR signaling. Ribosomal proteins (e.g., RPL7, RPL22, and RPL27A) and CRC-related genes such as APC, AXIN1, E2F4, MSH2, PMS2, and TP53 were highly enriched. In addition, differential pathways were observed between the CRC and control samples. Furthermore, 103 DIRAGs were reported in the SEREX antigen database, demonstrating our ability to identify known and new reactive antigens. We also found an overlap of 7 antigens with 48 “CRC genes.” These data indicate that immunomics profiling on protein microarrays is able to reveal the complexity of immune responses in cancerous diseases and faithfully reflects the underlying pathology.

MNS16A tandem repeat minisatellite of human telomerase gene: functional studies in colorectal, lung and prostate cancer MNS16A tandem repeat minisatellite of human telomerase gene: functional studies in colorectal, lung and prostate cancer

New minimal invasive diagnostic methods for early detection of lung cancer are urgently needed. It is known that the immune system responds to tumors with production of tumor-autoantibodies. Protein microarrays are a suitable highly multiplexed platform for identification of autoantibody signatures against tumor-associated antigens (TAA). These microarrays can be probed using 0.1 mg immunoglobulin G (IgG), purified from 10 µL of plasma. We used a microarray comprising recombinant proteins derived from 15,417 cDNA clones for the screening of 100 lung cancer samples, including 25 samples of each main histological entity of lung cancer, and 100 controls. Since this number of samples cannot be processed at once, the resulting data showed non-biological variances due to “batch effects”. Our aim was to evaluate quantile normalization, “distance-weighted discrimination” (DWD), and “ComBat” for their effectiveness in data pre-processing for elucidating diagnostic immune‑signatures. “ComBat” data adjustment outperformed the other methods and allowed us to identify classifiers for all lung cancer cases versus controls and small-cell, squamous cell, large-cell, and adenocarcinoma of the lung with an accuracy of 85%, 94%, 96%, 92%, and 83% (sensitivity of 0.85, 0.92, 0.96, 0.88, 0.83; specificity of 0.85, 0.96, 0.96, 0.96, 0.83), respectively. These promising data would be the basis for further validation using targeted autoantibody tests.

Telomere dysfunction is an early event in the development of prostate cancer and telomerase (TERT) activity is detectable in the majority of prostate cancers. Genetic variation in TERT and its regulatory elements may influence prostate carcinogenesis. MNS16A, a functional polymorphic tandem repeat minisatellite of TERT, has been studied in several malignancies. We determined MNS16A genotypes in an Austrian case–control study for the first time in the context of prostate cancer, comprising 1165 prostate cancer cases and 674 benign prostate hyperplasia controls with PCR. In addition to the five reported variable number of tandem repeats (VNTRs), we identified VNTR-212, a rare variant, for the first time in a European population. Multiple logistic regression analysis revealed no differences in genotype distribution between cases and controls. However, in stratified analysis, MNS16A VNTR-274 (OR = 0.25, 95% CI = 0.06–0.79, P = 0.016) and genotype 274/302 (OR = 0.13, 95% CI = 0.01–0.58, P = 0.005) were associated with a significantly decreased risk of prostate cancer in the age group >70 years. Our finding of a MNS16A genotype conferring a protective effect against prostate cancer in older men suggests a potential role of this polymorphism in prostate cancer susceptibility but demands to be validated in further studies.