Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
Mosaic loss of chromosome Y (LOY) in blood is linked to increased risk for morbidity and mortality in men. LOY is the most common acquired mutation and is associated with diseases such as cancer and Alzhemer's disease. We studied DNA, RNA and proteins in bulk, sorted-and single-cells in vivo and in vitro. We show that Alzheimer's disease and prostate cancer patients had more LOY in NK cells and CD4+ T-lymphocytes, respectively. Furthermore, gene expression was profoundly altered in cells with LOY in a pleiotropic fashion and autosomal genes important for normal immune cell functions showed LOY associated transcriptional effect. Proteomic analysis also indicated that LOY leaves a footprint in the plasma proteome. We provide the first mechanistic explanation for the associations between LOY in blood and risk for disease in other organs.Recent epidemiological analyses have challenged the view that LOY in blood cells is phenotypically neutral. Studies have identified increased risks for men with LOY in connection with all-cause mortality [8,9], Alzheimer's disease [10], various forms of cancer [8,[11][12][13], autoimmune conditions [14,15], age-related macular degeneration [16], cardiovascular disease [17], type 2 diabetes and obesity [9]. Furthermore, it has been known for centuries that males have a shorter life expectancy [18][19][20]. Hence, LOY as a male specific risk factor, showing reproducible associations with various common disorders, could help explaining this difference.LOY in blood is the most frequent post-zygotic mutation, detectable in 20% of the UK Biobank male population [21], reaching 40% in 80 years old males [22], and 57% in 93 years old males [23]. Furthermore, LOY is not restricted to the hematopoietic system, since it has also been described in other non-cancerous tissues, although with much lower frequencies [17,23]. Our understanding of why LOY occurs is also limited. Strong associations with age and smoking have been reported [8,10,24,25] and these factors are related to a continuously increasing mutational load throughout the genome in all somatic cells, eventually also affecting genes that are responsible for correct segregation of chromosomes. Inherited genetic predisposition for LOY has also been described [21,25,26].It is not known whether associations between LOY and increased risks for disease represent causal relationships, and if so, what the underlying mechanisms could be. The challenge that we address here is to move from epidemiological associations to mechanistic explanations on multiple levels of analysis such as DNA, mRNA and proteins. Specifically, we studied: (i) frequency of LOY in subsets of leukocytes from patients with prostate cancer (PC), Alzheimer's disease (AD) as well as controls; (ii) changes in transcriptomes of single cells and cellular subsets in bulk; and (iii) alterations of plasma protein levels in men with LOY. Different distribution of LOY in six types of sorted leukocytes among men with AD and PCStudies of associations between LOY and various outcomes hav...
Introduction: The quality of vesicourethral anastomosis (VUA) in laparoscopic radical prostatectomy (LRP) is associated with complications that could significantly affect quality of life.Aim: To compare different types of sutures (Chlosta's versus Van Velthoven versus V-Loc), used for VUA in LRP in terms of complication rates and continence recovery. Material and methods: Patients who underwent LRP between 2014 and 2018 in a tertiary center were enrolled in the study. Data were extracted from medical records. Urinary continence was assessed at 3, 6, 12 and 18 months after LRP. Propensity score weighted regression models were used to estimate the effect of sutures on outcomes.
The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver. The choice was based on the high incidence of these cancers and/or frequent fatal outcome. We also collect age-matched normal controls. Our still ongoing collection originates from five clinical centers and after nearly 2-year cooperation reached 1711 patients and controls, yielding a total of 23226 independent samples, with an average of 74 donors and 1010 samples collected per month. The predominant diagnosis is breast carcinoma, with 933 donors, followed by colorectal carcinoma (383 donors), prostate carcinoma (221 donors), bladder carcinoma (81 donors), exocrine pancreatic carcinoma (15 donors) and metachronous colorectal cancer metastases to liver (14 donors). Forty percent of the total sample count originates from macroscopically healthy cancer-neighboring tissue, while contribution from tumors is 12%, which adds to the uniqueness of our collection for cancer predisposition studies. Moreover, we developed two program packages, enabling registration of patients, clinical data and samples at the participating hospitals as well as the central system of sample/data management at coordinating center. The approach used by us may serve as a model for dispersed biobanking from multiple satellite hospitals. Our biobanking resource ought to stimulate research into genetic mechanisms underlying the development of common cancers. It will allow all available “-omics” approaches on DNA-, RNA-, protein- and tissue levels to be applied. The collected samples can be made available to other research groups.
Renal carcinoma is the 20th most common cancer worldwide. Clear cell renal cell carcinoma is the most frequent type of renal cancer. Even in patients diagnosed at an early stage, characteristics of disease progression remain heterogeneous. Up-to-date molecular classifications stratify the ccRCC samples into two clusters. We analyzed gene expression in 23 T1 or T3 ccRCC samples. Unsupervised clustering divided this group into three clusters, two of them contained pure T1 or T3 samples while one contained a mixed group. We defined a group of 36 genes that discriminate the mixed cluster. This gene set could be associated with tumor classification into a higher stage and it contained significant number of genes coding for molecular transporters, channel and transmembrane proteins. External data from TCGA used to test our findings confirmed that the expression levels of those 36 genes varied significantly between T1 and T3 tumors. In conclusion, we found a clustering pattern of gene expression, informative for heterogeneity among T1 and T3 tumors of clear cell renal cell carcinoma.
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