It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

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DNA methylation age of human tissues and cell types

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

WHO laboratory manual for the examination and processing of human semen

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.

Testicular dysgenesis syndrome ; an increasingly common developmental disorder with environmental aspects

Human mitochondrial DNA is widely used as tool in many fields including evolutionary anthropology and population history, medical genetics, genetic genealogy, and forensic science. Many applications require detailed knowledge about the phylogenetic relationship of mtDNA variants. Although the phylogenetic resolution of global human mtDNA diversity has greatly improved as a result of increasing sequencing efforts of complete mtDNA genomes, an updated overall mtDNA tree is currently not available. In order to facilitate a better use of known mtDNA variation, we have constructed an updated comprehensive phylogeny of global human mtDNA variation, based on both coding- and control region mutations. This complete mtDNA tree includes previously published as well as newly identified haplogroups, is easily navigable, will be continuously and regularly updated in the future, and is online available at http://www.phylotree.org. © 2008 Wiley-Liss, Inc.

/pdf/updated-comprehensive-phylogenetic-tree-of-global-human-448qrnrzdo.pdf

Updated Comprehensive Phylogenetic Tree of Global Human Mitochondrial DNA Variation

Promotion of high-quality education in andrology is the main mission and core activity of the European Academy of Andrology (EAA). The EAA fulfils this objective by multiple means, mainly through the EAAaccredited andrology training centres. These centres provide direct clinical education to young physicians interested in various aspects of andrology. Some of the centres have also a strong research profile in reproductive biology and pathology, and offer research training to young fellows (see EAA Centre profiles in this volume, DOI: 10.1111/ andr.13245). As far the direct educational activities are concerned, the most successful are the recurrent ‘EAA schools’. Between 2016 and 2020, four EAA Schools have been established, each one with a distinct focus and educational programme, in most cases comprising ‘handson’ training in various diagnostic procedures required for andrological work-up. The EAA schools have been well-attended by trainees from many European countries, but also from remote countries of theworld, including Australia, Chile,Malaysia, Indonesia, USA. Below, the profiles and objectives of the EAA Schools are summarized. The EAA is supporting EAA members wishing to visit the EAA Centres for training or to attend the EAA Schools with scholarships and travel grants. In the period 2016–2021, ten young fellows received scholarships, briefly summarized in this article.

Educational activities of the European Academy of Andrology: EAA Schools and Scholarships

1Centre of ReproductiveMedicine and Andrology, University Hospital Münster, Münster, Germany 2Professor Emeritus of Endocrinology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy 3Emeritus Professor ofMedicine and Endocrinology, Division of Endocrinology, Diabetes &Gastroenterology, School ofMedical Sciences, Faculty of Biology, Medicine andHealth, University ofManchester, Manchester, UK 4Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland 5Department of Pediatrics, Turku University Hospital, Turku, Finland 6Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Italy

History of the European Academy of Andrology

Una ridotta fertilita e presente in circa il 5–7% di tutti gli uomini e cio puo essere dovuto a fattori congeniti o acquisiti, a loro volta suddivisibili in fattori pre-testicolari, testicolari e post-testicolari. La causa di infertilita piu frequente (circa il 75%) e da attribuirsi a fattori testicolari. Nonostante i progress i fatti, soprattutto nell’ambito della genetica, nel 50% dei casi l’infertilita maschile e definita “idiopatica” in quanto l’eziologia rimane sconosciuta. A parte qualche eccezione, l’unica terapia applicabile per le forme gravi di infertilita maschile e la fecondazione assistita. Una diagnostica completa e importante per: a) identificare le forme trattabili/reversibili o le forme che si associano a rischi per la salute generale; b) selezionare i pazienti che possono effettuare tecniche di riproduzione assistita; c) indirizzare questi pazienti a un’appropriata consulenza genetica preimpianto, o alla diagnosi prenatale per la salvaguardia della salute dei futuri nascituri.

Infertilità maschile: aspetti patogenetici e clinici


 
 
 Does cancer increase sperm DNA fragmentation (sDF) level by increasing oxidative stress in human spermatozoa?
 
 
 
 Cancer increases both sDF and oxidative stress, but further studies are necessary to understand whether higher levels of ROS are responsible for sperm DNA damage.
 
 
 
 In recent years, it has been emerging that not only oncological therapies but also cancer itself can induce abnormal spermatogenesis. In addition, several Authors reported that occurrence of malignancy provokes also increases of sperm DNA damage, although such finding was not confirmed by others and the possible mechanisms responsible for such damage are presently unknown
 
 
 
 This was a prospective observational study conducted from 2018 to today, conducted in 102 patients affected by cancer and in 66 control subjects.
 
 
 
 We recruited 102 patients affected by cancer and 66 male partners of infertile couples as control subjects, in the Andrology Clinic of University of Florence. Control subjects were normozoospermic with absence of leukocytospermia, semen viscosity, smoking habit and recent antibiotic therapies. In the recruited men, we evaluated standard semen parameters, sperm DNA Fragmentation with SCD (Sperm Chromatin Dispersion) Test and oxidative stress as percentage of viable spermatozoa with MitoSOX™ Red labeling on total viable spermatozoa.
 
 
 
 We found poorer standard semen parameters (sperm motility, concentration and number) in cancer patients (both testicular and hematological ones) with respect to control group, whereas no differences were observed between the two types of cancer. Testicular, but not hematological patients, were younger than control subjects. No difference was seen in the other tested characteristics (sperm morphology, abstinence, semen volume and pH, BMI). Regarding sDF, we found higher median values [IQR] in cancer patients (total: 22.25[17.00-25.95], n = 68; hematological: 23.00[20.13-26.38], n = 28; testicular: 21.13[16.13-25.73], n = 40) vs control subjects (12.50[8.25-14.75], n = 53); p < 0.05, test U di Mann-Whitney. In addition, the amount of sperm oxidative stress was dramatically higher in patients with cancer (total:38.92[24.90-58.87], n = 79; hematological: 38.85[24.98-50.77], n = 34; testicular: 38.92[20.59-63.59], n = 45) vs control subjects (11.50[8.38-17.20], n = 62); p < 0.05, test U di Mann-Whitney. We also studied the occurrence of a correlation between levels of sDF and oxidative stress. We found a sharp correlation when both cancer patients and control subjects were analysed (Spearman coefficient = 0.62, p < 0.001, n = 103), but such correlation was completely lost when only cancer patients were considered (Spearman coefficient = 0.10, p > 0.05, n = 50). This finding suggests that mechanisms different from ROS attack to DNA could explain the increase of sDF levels in cancer patients.
 
 
 
 The study did not investigate, because of scarce availability of semen samples from cancer patients, other possible mechanisms (i.e apoptosis, defects in sperm chromatin maturation, failure in DNA system repair) which could cause the observed increase of sperm DNA damage in such patients.
 
 
 
 Cancer patients show high levels of both sDF and oxidative stress. This finding rises concern, as cancer patients cryopreserve semen for using it with Assisted Reproductive Tecnhologies and both parameters represent a threat for natural and assisted reproduction. In addition, emerging evidence suggest that oxidative stress may alter sperm epigenome.
 
 
 
 not applicable


P-068 Oxidative stress and DNA fragmentation of spermatozoa in patients with cancer

Itumori a cellule germinali del testicolo rappresentano la neoplasia maligna piu frequente nei maschi fra i 15 e i 40 anni di eta, con un progressivo aumento di incidenza negli ultimi decenni. L’eziologia e multifattoriale e riconosce un’importante componente genetica e ambientale. Il trattamento prevede l’orchiectomia ed eventuale chemio/radioterapia adiuvante che assicurano la guarigione definitiva in circa il 95% dei casi. Sebbene un recupero della spermatogenesi avvenga in oltre l’85% dei soggetti a due anni dalla terapia, e altamente consigliata la crioconservazione del liquido seminale pre-terapia citostatica.

Csilla Krausz

Papers

Educational activities of the European Academy of Andrology: EAA Schools and Scholarships

History of the European Academy of Andrology

Infertilità maschile: aspetti patogenetici e clinici

P-068 Oxidative stress and DNA fragmentation of spermatozoa in patients with cancer

Tumori testicolari: aspetti eziopatogenetici