Genetic susceptibility and molecular landscape in familial, bilateral and sporadic patients with testicular germ cell tumour (TGCT)

Testicular Germ Cell Tumours (TGCT) are the most common cancer type in young men. Even though a high heritability is described for TGCT, no high susceptibility genes have been identified; instead, a polygenic susceptibility model is accepted. Familial (1-2%), bilateral (1-5%) and sporadic TGCT cohorts have longer been studied together without assessing different genetic implication. There are two main histologies, the seminoma and the non-seminoma tumours, and no genetic differences have been described between them. Here, we have evaluated TGCT patients considering different histologies and cohorts, to uncover the genetic relevance through the clinical evaluation of 55 familial, 33 bilateral and 527 sporadic patients, the germline WES of 38 familial, 4 bilateral and 8 sporadic patients, and the somatic WES of 1 family, 7 bilateral tumours and 4 sporadic tumours, in order to identify moderate susceptibility genes and pathways involved in the disease, and to stablish genetic differences between different cohorts and histologies. Our results showed that familial and bilateral patients develop TGCT significantly earlier than sporadic patients. In addition, an aggregation study showed that familial and bilateral patients also have a lower percentage of relatives with other tumour types different to TGCT compared to the sporadic patients. This suggests that familial and bilateral TGCT patients have a stronger genetic background and should be studied as a single group that might involve a tissue-specific syndrome. On the other hand, malfunctions in constitutional mechanisms in patients with sporadic tumours might predispose to cancer in any tissue. The Gene Ontology study with the variants obtained from WES at the germline level uncovered that glycosylation (a post-translational modification) was over-represented in all the cohorts of patients, and might be involved in the disease. In addition, 5 glycosylation genes carried variants in the three cohorts of patients and are expressed in the testicular tissue (GXYLT1, MUC16, MUC4, MUC20 and MUC21), which is in agreement with the tissue-specific syndrome. At the somatic level, the Gene Ontology showed that the glycosylation pathway was also over-represented in the three cohorts of patients, and there were 4 genes that are expressed in the testicular tissue and carried variants in the three cohorts of patients (MUC16, MUC4, MUC20 and MUC21). Finally, an intrapatient and an interpatient analysis carried out in the bilateral cohort comparing the similarities and the differences between the histologies, showed that the bilateral patients presented more similarities in the somatic genes carrying variants when tumours with different histologies within each patient were compared, than when tumours with the same histologies from different patients were gathered. These results are in agreement with the age of onset and the aggregation study, as they support the idea that in the bilateral patients there is a stronger germline genetic background. In summary, even if we found differences between the three cohorts of patients when the age of onset and the aggregation with other tumour types was analysed, we did not find major genetic differences between the familial, the bilateral, and the sporadic TGCT patients, as they all presented an over-representation of genes carrying variants involved in the glycosylation pathway both at the germline and at the somatic level. Glycosylation is suitable with our results, as it is a constitutional pathway (sporadic cohort), but it is also necessary in the spermatogenesis process (familial and bilateral cohorts). Finally, the glycosylation pathway was also found over-represented in both seminoma and non-seminoma tumours