Department of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 211 Bailey Road, West Henrietta, NY 14586, USA.
Genes (Basel). 2022 Mar 26;13(4):591. doi: 10.3390/genes13040591.
Germline disruptive variants in () predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5CD10 B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the variant was germline. This likely pathogenic loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic variants (i.e., autosomal dominant tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the genetic locus (7q31.33).
胚系功能获得性突变可导致多种癌症，包括黑色素瘤、慢性淋巴细胞白血病（CLL）、霍奇金淋巴瘤、骨髓增生性肿瘤和神经胶质瘤。我们报告了首例源自胚系 突变的脾边缘区淋巴瘤（SMZL）病例：一名 65 岁男性，有广泛的癌症病史，包括黑色素瘤和甲状腺乳头状癌，表现为循环异型淋巴细胞增多。骨髓活检显示 20%的 CD5CD10B 细胞淋巴瘤受累，难以分类。在对他的低级别淋巴瘤进行临床检查时，靶向下一代测序（NGS）发现 p.I49Mfs*7（NM_015450：c.147delT）的变异等位基因频率（VAF）为 51%。皮肤成纤维细胞的 NGS 证实了 突变是胚系的。这种可能的致病性 功能获得性突变之前仅在一名患有神经胶质瘤的患者的胚系中报道过一次，可能代表与家族性癌症相关的最具危害性的胚系 突变之一。与胚系致病性 突变（即常染色体显性肿瘤易感性综合征）相关的癌症谱可能需要扩展到包括 SMZL，这种疾病通常与染色体 7q 缺失有关： 基因座的位置（7q31.33）。
