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.

/pdf/dna-methylation-age-of-human-tissues-and-cell-types-528gzlrlkl.pdf

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

FSH Treatment in Male Infertility

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online) 

The X chromosome and male fitness

Cancer impairs spermatogenesis, whereas results on sperm DNA integrity are controversial and no data are available about sperm oxidative stress. In cancer patients, we detected sperm DNA fragmentation (sDF) and both viable (ROS production in viable sperm fraction/viable spermatozoa) and total (ROS production in viable sperm fraction/total spermatozoa) oxidative stress. We found that cancer (22.50 (17.00–26.75)%, n = 85) increased sDF with respect to the control groups in both normozoospermic subfertile patients (NSP) (12.75 (8.63–14.88)%, n = 52, p < 0.001) and in healthy donors (HD) (8.50 (7.00–14.00)%, n = 19, p < 0.001). The induction of viable oxidative stress (n = 96) with cancer was even higher: 36.60 (24.05–58.65)% versus 11.10 (8.63–14.90)% in NSP (p < 0.001) and 9.60 (8.00–14.03)% in HD (p < 0.001). Similar, albeit lower, differences were found for total oxidative stress. SDF sharply correlated to viable oxidative stress when we considered all subjects (cancer patients and controls) (r = 0.591, p < 0.001, n = 134), but no correlation was found when only cancer patients were studied (r = 0.200; p > 0.05, n = 63). In conclusion, cancer significantly increases sDF and sperm oxidative stress levels. Additional mechanisms to oxidative attack might be responsible for increased sDF in cancer patients. Because sperm oxidative stress might affect the outcomes of sperm cryopreservation, of cancer treatments and of sperm epigenoma, the detection of oxidative stress could be of help in managing the reproductive issues of cancer patients.

/pdf/testicular-and-haematological-cancer-induce-very-high-levels-2vl3ag9j.pdf

Testicular and Haematological Cancer Induce Very High Levels of Sperm Oxidative Stress

Dear EAA Members, In this report, we summarize our activities during the entire year 2019 and announce of our plans for the 2020. The new Executive Council (elected at the end of 2018) and I are proud of the achievements and looking forward to further growth of the Academy and improving service to the andrology community in Europe and beyond. Our top priority is andrology education, and in 2019, we organized two recurrent and very popular EAA Schools: 3rd EAA School in Ultrasound in Florence and Rome, continuing to the 5th edition in 2020, and 2nd EAA Winter School in Testicular Histology in Zagreb. We also launched the first EAA School in Genetics of Male Infertility, which was successfully organized in Tartu. In March 2020, we will hold another new EAA Andrology School, in Budapest; this one tailored to prepare physicians to pass the examination for the EAA Clinical Andrologist certificate. This course will be held back-to-back with an open meeting on ‘Androgen therapies’, which will review state-of-the-art of this topic (see the 2020 Event Calendar at the end of the report). In addition to our own Schools, we continued to promote and support courses and meetings within the broad field of andrology, either organized by EAA Training Centres or other academic institutions. The full list of the supported events is included in this report. On behalf of the Executive Council, I thank the directors and staff of the EAA Training Centres for their dedication and work on promoting andrology. During 2019, we have re-accredited several centres, listed in this report, and we are planning to accredit new training centres in 2020. EAA actively promotes also basic andrology research and education, and we provided support for the annual meeting of the Network of Young Researchers in Andrology (NYRA), held in connection with the Molecular Andrology Workshop in September 2019 in Giessen. The EAA will also support the upcoming European Testis Workshop (ETW2020) in Spain. In 2019, we have expanded contacts and collaboration with related learned societies. A new partner society is the European Society of Sexual Medicine (ESSM), and I have signed a Memorandum of Understanding on educational aspects with the ESSM President, Dr Cobi Reisman. Concerning our partnership with the European Society of Endocrinology (ESE), we organized the second pre-congress practical andrology course in connection with the European Congress of Endocrinology (ECE 2019) in Lyon. According to our earlier agreement, an EAA symposium in andrology will be in the programme of the ECE 2020 in Prague. We have strengthened our collaboration with the American Society of Andrology (ASA) and signed an agreement regarding exchange lectures and joint supervision of Andrology, the official journal of both societies. We were all happy that in 2019, Andrology regained the top position in the field, as detailed in this report. This journal has been the perfect medium to disseminate the EAA-endorsed clinical guidelines, which are prepared by foremost experts in the discussed areas of andrology. In 2019, we have published the guidelines on gynaecomastia and other texts are in the pipeline. Another mission of EAA is to increase public awareness in andrology, and hence, the members of the Male Health Awareness Committee have advanced preparation of a new website addressed to lay public, expected to be launched in 2020. To improve our outreach to the members and collaborators, we have increased frequency of communications and are now present on Twitter and Facebook. We are looking forward with optimism and planning many activities for 2020, which will culminate with the big event in December:

Csilla Krausz

Papers

FSH Treatment in Male Infertility

The X chromosome and male fitness

Testicular and Haematological Cancer Induce Very High Levels of Sperm Oxidative Stress

European Academy of Andrology Annual Report 2019.

DDB1- and CUL4-associated factor 12-like protein 1 (Dcaf12l1) is not essential for male fertility in mice.