gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study

Abstract

The association between impaired spermatogenesis and TGCT has stimulated research on shared genetic factors. Y chromosome-linked partial AZFc deletions predispose to oligozoospermia and were also studied in TGCT patients with controversial results. In the largest study reporting the association between gr/gr deletion and TGCT, sperm parameters were unknown. Hence, it remains to be established whether this genetic defect truly represents a common genetic link between TGCT and impaired sperm production. Our aim was to explore the role of the following Y chromosome-linked factors in the predisposition to TGCT: (i) gr/gr deletion in subjects with known sperm parameters; (ii) other partial AZFc deletions and, for the first time, the role of partial AZFc duplications; (iii) DAZ gene dosage variation. 497 TGCT patients and 2030 controls from two Mediterranean populations with full semen/andrological characterization were analyzed through a series of molecular genetic techniques. Our most interesting finding concerns the gr/gr deletion and DAZ gene dosage variation (i.e., DAZ copy number is different from the reference sequence), both conferring TGCT susceptibility. In particular, the highest risk was observed when normozoospermic TGCT and normozoospermic controls were compared (OR = 3.7; 95% CI = 1.5-9.1; p = 0.006 for gr/gr deletion and OR = 1.8; 95% CI = 1.1-3.0; p = 0.013 for DAZ gene dosage alteration). We report in the largest European study population the predisposing effect of gr/gr deletion to TGCT as an independent risk factor from impaired spermatogenesis. Our finding implies regular tumour screening/follow-up in male family members of TGCT patients with gr/gr deletion and in infertile gr/gr deletion carriers.

Y chromosome copy number variation and its effects on fertility and other health factors: a review

“…This has been seen in the development of gonadoblastoma in Turner's syndrome patients (81) as well in other germ cell tumors in patients with disorders of sexual development (82). The previously discussed gr/gr deletion has been implicated in the development of testicular germ cell tumors (83,84). Beyond the testicle, loss of the Y chromosome in peripheral blood has been found to be a risk factor for the development of colorectal and prostate cancer (85).…”

Y-Chromosome Microdeletions: A Review of Prevalence, Screening, and Clinical Considerations

“… 64 Partial AZFc (gr/gr) deletions may also predispose men to testicular germ cell tumors, particularly in normospermic carriers. 65 Screening for partial AZFc deletions, such as gr/gr, may help prevent these negative clinical outcomes at little additional cost. This practice may be particularly beneficial in certain populations (ie Spanish and Italian men), in which previous research has consistently shown associations between gr/gr and infertility.…”

Germ cell determination and the developmental origin of germ cell tumors

“…DAZ family DAZ: case-control studies of gr/gr men find increased relative risk of GCT (Moreno-Mendoza et al, 2019;Nathanson et al, 2005). DAZL: GWAS (Ruark et al, 2013).…”

“…De novo structural rearrangements of the Y chromosome regularly affect DAZ copy number and are a significant cause of spermatogenic failure (Rozen et al, 2012). One common Y-chromosome rearrangement, the gr/gr deletion, removes two copies of DAZ and is associated with an elevated GCT risk, particularly in men with a family history of GCTs (Moreno-Mendoza et al, 2019;Nathanson et al, 2005;Repping et al, 2003). Furthermore, the autosomal gene DAZL is directly implicated in the heritability of GCTs by GWAS (Ruark et al, 2013).…”