Broader Familial Cancer Risk in Relatives of Testicular Cancer Patients: Insights From Two Mediterranean Populations

Background: Familial clustering of testicular germ cell tumour (TGCT) is well-established, whereas the risk of non-testicular cancer among relatives remains inconsistent across studies. Objective: To evaluate the overall and site-specific cancer risk among first-degree relatives and grandparents of TGCT patients compared to cancer-free controls. Materials and Methods: We enrolled 1453 subjects from two andrology centres: 628 TGCT patients, 367 oncohaematological (OH) malignancy patients, and 458 cancer-free controls undergoing vasectomy. Family cancer history was collected through standardized questionnaires documenting cancer occurrence and type in first-degree relatives and grandparents, categorizing malignancies into 16 specific groups. Results: Positivity for family history of cancer was significantly higher in the TGCT cohort compared with controls (p < 0.001), whereas no significant increase was observed in the OH cohort. Conversely, analyses based on tumour rates (total number of cancers) revealed significantly higher tumour burden in both TGCT and OH cohorts compared to controls (p < 0.001). Site-specific analysis in TGCT patients’ relatives showed significantly higher risk of TGCT (OR: 6.11, 1.83–20.39), pancreas (OR: 9.05, 2.17–37.66), thyroid (OR: 6.32, 1.45–27.55), uterine (OR: 4.82, 1.08–21.44) and urinary tract cancers (OR: 3.07, 1.43–6.58). Both TGCT and OH relatives showed a significant risk for breast, gastrointestinal and lung cancer. Discussion: We observed notable familial clustering of cancers, not limited to TGCT but spanning several malignancies. Many of the observed associations involve cancers within the Lynch syndrome spectrum, suggesting TGCT as a potential atypical manifestation of Lynch-associated tumorigenesis. Nonetheless, the familial aggregation may also reflect gene–environment interactions and susceptibility loci related to hormone-dependent pathways, as evidenced by the elevated risks of breast and uterine cancers in TGCT families. One of the major limitations of our study, like many others relying on familial data, is the potential for recall bias in patient-reported family histories. Conclusions: Our study demonstrates a significant familial cancer risk in TGCT patients, underscoring the importance of detailed family history collection and the need for further studies to clarify the contributing genetic and environmental determinants.