A germline mutation in PBRM1 predisposes to renal cell carcinoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Many familial renal cell carcinoma (RCC) cases lack explanation from known genes or environmental factors.
• The PBRM1 gene, a known tumor suppressor, is frequently mutated in sporadic clear cell RCC (ccRCC).

Purpose of the Study:

• To investigate the role of the PBRM1 gene in unexplained familial ccRCC.
• To identify novel genetic factors contributing to hereditary RCC.

Main Methods:

• Sequencing of the PBRM1 gene in 35 unrelated patients with familial ccRCC.
• Analysis of mutation co-segregation within affected families.
• Somatic mutation analysis, including loss of heterozygosity and protein expression, in renal tumors.

Main Results:

• A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) in PBRM1 was identified in one patient with familial ccRCC.
• The mutation co-segregated with ccRCC in the patient's affected mother, sister, and niece, consistent with autosomal-dominant inheritance.
• Somatic studies confirmed loss of heterozygosity and protein expression in the patient's renal tumors.

Conclusions:

• This study provides the first evidence that inherited PBRM1 mutations can predispose individuals to RCC.
• Further international studies are required to determine the prevalence of PBRM1 mutations in RCC susceptibility and estimate penetrance.
• Integration of PBRM1 into routine clinical practice for RCC risk assessment may be considered following further research.