Malignant germ cell tumours of childhood: new associations of genomic imbalance

Abstract

Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p-(P ¼ 0.003), 3p þ (P ¼ 0.02), 4qÀ (P ¼ 0.07) and 6qÀ (P ¼ 0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5 -16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P ¼ 0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities.

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

“…A direct comparison of paediatric and adult samples in the same study is needed to determine how reliable these apparent differences might be. In addition, all childhood YSTs shared similar cytogenetic abnormalities and expression profiles regardless of age (Palmer et al 2007, Frazier et al 2012. This is in contrast to the classical separation of infantile YSTs from other malignant GCTs occurring in older children and adults, based on epidemiological, clinical and genetic features (Veltman et al 2003, Oosterhuis & Looijenga 2005.…”

“…This is in contrast to the classical separation of infantile YSTs from other malignant GCTs occurring in older children and adults, based on epidemiological, clinical and genetic features (Veltman et al 2003, Oosterhuis & Looijenga 2005. Differences in the genetics, clinical aspects and expression profiles of adult and paediatric GCTs suggest that the mechanisms underlying their formation may be different (Veltman et al 2003, Palmer et al 2007.…”

“…Gain of chromosome 12p is a consistent feature of adult GCTs but is found at a lower incidence in childhood malignant tumours, which instead display unique cytogenetic abnormalities (loss on 1p, 4q and 6q in YSTs) (Palmer et al 2007, Frazier et al 2012. Gene expression analysis has suggested that childhood GCTs may have different expression profiles compared to their adult counterparts; the separation was especially striking between adult and paediatric YSTs (Palmer et al 2008).…”

Age‐related biological features of germ cell tumors

“…It was subsequently established that i(12p) occurs in 80% of adult TGCTs, while gain of 12p genomic material is invariably present in the other 20% of cases (Looijenga, 2001). Indeed, i(12p) appears to be a characteristic cytogenetic event in both gonadal and extragonadal adult GCTs (Oosterhuis et al, 1997;Bussey et al, 1999;Kraggerud et al, 2000;Schneider et al, 2002;McKenney et al, 2007;Palmer et al, 2007). By contrast, a gain of 12p was until recently thought to occur only rarely in paediatric cases.…”

“…This led the authors to postulate that gain of 12p was significantly associated with patient age and, accordingly, may relate to the physiological changes brought about by the onset of puberty. By contrast, a more recent paediatric (0-16y) study (Palmer et al, 2007) analysed 11 seminomas, 22 YSTs and one metastatic EC from a range of anatomical sites from 12 male and 22 female patients, including a large proportion of ovarian GCTs. Chromosome 12p gain was identified in 44% of cases, with an incidence increasing with age (29% of those <5y, compared with 53% in those 5-16y).…”