DNA Methylation Analysis Reveals Distinct Methylation Signatures in Pediatric Germ Cell Tumors

Background: Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. Methods: We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Results: Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q \u3c 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Conclusion: Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy

Paediatric extracranial germ-cell tumours.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S1470-2045(15)00545-

Ovarian cancer risk factors by tumor aggressiveness : An analysis from the Ovarian Cancer Cohort Consortium

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in = 35 vs. 20 to <25 kg/m(2), 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.Peer reviewe

Molecular epidemiology of colorectal cancer: Mechanisms of risk and clues towards chemoprevention.

Both genetic and environmental factors play a large role in the etiology of colorectal cancer. In this dissertation, I used data from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population based case-control study of colorectal cancer, to better understand mechanisms of risk, models of inherited susceptibility and chemoprevention of colorectal cancer. Chemopreventive agents for colorectal cancer have been highly sought with limited success to date. Data from the MECC study suggest that the statin drugs, a class of drugs which are used effectively to treat hypercholesterolemia, may have chemopreventive activity. Use of these drugs for at least five years was associated with a significantly reduced risk of colorectal cancer after adjusting for other known risk factors for CRC (OR = 0.53, 95% CI 0.38 - 0.74). Several potential mechanistic explanations exist to support this association, although further studies will be required to elucidate the relevant mechanisms. These data suggest that statins should be evaluated in chemoprevention and therapeutic clinical trials. In a second study, I used molecular techniques to evaluate the mechanism of risk associated with a candidate susceptibility allele, BLM ASH. This mutation was previously shown to be associated with risk of CRC with several potentially relevant mechanistic explanations including either loss of the normal allele in the tumor tissue or haploinsufficiency. Data from tumor tissue obtained from heterozygous mutation carriers enrolled in the MECC study do not provide compelling evidence to support either mechanism. Further analyses are required to provide a more definitive conclusion regarding this association. The kin-cohort design has been proposed as an alternative to traditional case-control and cohort measures to evaluate inherited susceptibility to cancer in population-based studies. Here, I used this design to evaluate inherited susceptibility to cancer associated with two candidate susceptibility alleles in the MECC study, APC I1307K and BLM ASH. The evidence for an association between I1307K and both prostate and breast cancer was not compelling. We were able to detect an association between I1307K and colorectal cancer; although the association was reduced when compared with the estimate obtained using standard case-control measures. Overall, these data suggest that measurement error and small numbers of events may limit the usefulness of this technique in population-based designs.Ph.D.Health and Environmental SciencesPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125197/2/3186736.pd

Medical conditions and modifiable risk factors for myelodysplastic syndrome: A systematic review

Background: The aim of this systematic review was to evaluate medical conditions and modifiable risk factors for myelodysplastic syndromes (MDS) using the 2001 or 2008 World Health Organization (WHO) diagnostic criteria. Methods: PubMed, MEDLINE, and Scopus databases were searched for studies published between January 2001 and August 2017. Study characteristics and findings were abstracted for each article. Results: Thirteen articles (4 cohort, 9 case-control) met the inclusion criteria. Smoking and alcohol use were each evaluated as potential MDS risk factors in four studies. Body mass index and anemia were each evaluated in two studies. Other potential risk factors evaluated in single studies included physical activity, dietary intake (tea, isoflavones, meat, fruit, or vegetables), history of allergies, autoimmune disorders and community-acquired infections, and use of antituberculosis drugs, traditional Chinese medicines, or hair dyes. Conclusions: Higher BMI, smoking, a history of autoimmune disorders, community-acquired infections, history of anemia, and use of antituberculosis drugs were associated with higher risk of MDS. Vigorous physical activity and tea and dietary isoflavone intake were associated with lower MDS risk. These findings suggest no association between the other factors and risk of MDS. Impact: Research on risk factors for MDS is limited, and further research in larger studies is needed

Children\u27s Oncology Group\u27s 2023 blueprint for research: Germ cell tumors.

Extracranial germ cell tumors (GCT) are a biologically diverse group of tumors occurring in children, adolescents, and young adults. The majority of patients have excellent outcomes, but treatment-related toxicities impact their quality of survivorship. A subset of patients succumbs to the disease. Current unmet needs include clarifying which patients can be safely observed after initial surgical resection, refinement of risk stratification to reduce chemotherapy burden in patients with standard-risk disease, and intensify therapy for patients with poor-risk disease. Furthermore, enhancing strategies for detection of minimal residual disease and early detection of relapse, particularly in serum tumor marker-negative histologies, is critical. Improving the understanding of the developmental and molecular origins of GCTs may facilitate discovery of novel targets. Future efforts should be directed toward assessing novel therapies in a biology-driven, biomarker-defined, histology-specific, risk-stratified patient population. Fragmentation of care between subspecialists restricts the unified study of these rare tumors. It is imperative that trials be conducted in collaboration with national and international cooperative groups, with harmonized data and biospecimen collection. Key priorities for the Children\u27s Oncology Group (COG) GCT Committee include (a) better understanding the biology of GCTs, with a focus on molecular targets and mechanisms of treatment resistance; (b) strategic development of pediatric and young adult clinical trials; (c) understanding late effects of therapy and identifying individuals most at risk; and (d) prioritizing diversity, equity, and inclusion to reduce cancer health disparities and studying the impacts of social determinants of health on outcomes