Genomic characterization of lymphomas in patients with inborn errors of immunity.

Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.

[Multiple gastrointestinal stromal tumors in neurofibromatosis type 1]. / Multiple gastrointestinale Stromatumoren bei Neurofibromatose Typ 1.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are generally rare, but appear more frequently in patients with neurofibromatosis type 1. Mostly asymptomatic, GIST can also cause relevant clinical appearances such as gastrointestinal bleeding, obstruction, or invagination. In recent years, a significant expert knowledge was gained in biology and treatment of these tumors. CASE REPORT: The case of a 50-year-old man with a history of neurofibromatosis type 1 and acute gastrointestinal bleeding is described. In the index upper endoscopy an ulcerated tumor of the proximal small bowel was found. The histopathologic examination showed a GIST. Segmental small bowel resection was carried out. Over the course of 1 year, there has been no evidence of a recurrence, metastases, or metachronous GIST. CONCLUSION: Considering the distinct biology of GIST in patients with neurofibromatosis type 1, the recommendation for a generous endoscopic examination or a routine endoscopy in this population is discussed.

Clear cell sarcoma-like tumor with osteoclast-like giant cells in the small bowel: further evidence for a new tumor entity.

Most mesenchymal neoplasms of the gastrointestinal tract belong to the category of gastrointestinal stromal tumors (GISTs) and are characterized by the immunohistochemical expression of KIT receptor. In cases without detectable KIT receptor expression several differential diagnoses have to be taken into consideration. Here, we report a case of a 41-year-old man with a tumor of the small bowel composed of large epithelioid tumor cells arranged in solid and alveolar sheets including scattered osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells expressed strongly S-100 protein, vimentin, and to a lesser extent, bcl-2. HMB-45, melan-A, KIT receptor, desmin, smooth-muscle actin, and CD-34 were not detectable. Ki-67 index was 20%. The diagnosis was established by 2 different FISH strategies demostrating the presence of a t(12;22)(q13;q12) translocation, the diagnostic hallmark of clear cell sarcoma of soft parts. Our results provide further evidence for the existence of a new tumor entity designated gastrointestinal clear cell sarcoma with osteoclast-like giant cells. The diagnosis of this entity should be considered in the presence of S-100-positive tumors of the gastrointestinal tract containing multinucleated giant cells and can be established by FISH analysis.