DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

Abstract

Germ cell tumours (GCTs) are a diverse group of neoplasms that can be histologically subclassified as either seminomatous or non-seminomatous. These two subtypes have distinct levels of differentiation and clinical characteristics, the non-seminomatous tumours being associated with poorer prognosis. In this article, we review how different patterns of aberrant DNA methylation relate to these subtypes. Aberrant DNA methylation is a hallmark of all human cancers, but particular subsets of cancers show unusually high frequencies of promoter region hypermethylation. Such a 'methylator phenotype' has been described in non-seminomatous tumours. We discuss the possible cause of distinct methylation profiles in GCTs and the potential of DNA methylation to provide new targets for therapy. We also consider how recent developments in our understanding of this epigenetic modification and the development of genome-wide technologies are shedding new light on the role of DNA methylation in cancer aetiology.Reproduction (2013) 146 R49-R60

Aberrant Reduction of MiR-141 Increased CD47/CUL3 in Hirschsprung's Disease

“…DNA methylation, as a major modification of epigenetic modification, broadly participated in human development process and a variety of diseases. Abnormal DNA methylation is considered to be a hallmark of human tumors [12]. Abnormal DNA methylation was found closely related to human life processes such as diet [13], infertility [14].…”

Survival differences by race/ethnicity among children and adolescents diagnosed with germ cell tumors

“…5,6 GCTs are heterogeneous with regard to both tumor location and histology, which vary by sex, age at diagnosis and race/ethnicity and also impact survival. 2,[6][7][8][9][10][11][12] For example, tumors of mixed histology display a higher rate of death than other histologic subtypes in females. 12 In males diagnosed with testicular cancer at ages <40 years, nonseminoma histology is associated with a higher risk of death than seminoma.…”

“…GCTs are heterogeneous with regard to both tumor location and histology, which vary by sex, age at diagnosis and race/ethnicity and also impact survival . For example, tumors of mixed histology display a higher rate of death than other histologic subtypes in females .…”

Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children’s Oncology Group

“…2 Extragonadal tumours are more common in the paediatric age range compared to adolescent or young adult tumours, and are thought to arise from abnormal migration of PGCs during embryogenesis. 8,9 As germ cells undergo extensive epigenetic reprogramming during the embryonic and early developmental periods, 6,10–12 understanding differences in methylation patterns between histologic subtypes may shed light on aetiologic variation by histology as we work toward identifying important windows of exposure.…”

“…12,13 In general, paediatric tumours are less likely than adult cancers to result from the accumulation of mutations or DNA damage possibly due to the short latency period from birth to cancer diagnosis. 6,14 Therefore, other mechanisms such as aberrant DNA methylation in GCT development may play an essential role in GCT initiation and progression, particularly among paediatric GCTs.…”