Gene

Carcinoma

Biology

Kidney cancer

Somatic cell

Mutation

Cancer research

Germline

Renal cell carcinoma

Genetics

Germline mutation

Loss of heterozygosity

Internal medicine

Medicine

Allele

Immunohistochemistry

Cancer

Pathology

Journal of Clinical Pathology

Aims Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. Methods Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. Results All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH ; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. Conclusions HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas