首页 > 期刊杂志 > 正文

TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype.

TCEB1突变肾细胞癌:独特的基因与形态学亚型

Hakimi AA,Tickoo SK,Jacobsen A,Sarungbam J,Sfakianos JP,Sato Y,Morikawa T,Kume H,Fukayama M,Homma Y,Chen YB,Sankin AI,Mano R,Coleman JA,Russo P,Ogawa S,Sander C,Hsieh JJ,Reuter VE

Abstract

Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.

摘要

综合序列分析发现肾透明细胞癌中一组肿瘤伴有特征性TCEB1基因(有助于VHL-缺氧诱导因子复合物的基因)热点突变。我们收集11例伴TCEB1突变的肿瘤,并扩大研究范围以评估是否应将其视为不同于透明细胞肾细胞癌和透明细胞乳头状肾细胞癌的独特的病变实体。所有肿瘤以TCEB1 Y79C/S/F/N或A100P热点突变为特征。 肿瘤组织形态和免疫组织化学特点由两位具有丰富经验的泌尿生殖病理医生进行评估。就肿瘤的临床及病理特征、染色体拷贝数量改变、突变和表达特征等方面与TCEB1野生型肿瘤进行比较。所有TCEB1突变型肿瘤显示VHL和PBRM1为野生型及独特拷贝数量,包括8号染色的杂合性缺失,TCEB1(8q21.11)位于该染色体。所有肿瘤缺乏透明细胞肾细胞癌独特的3p缺失和含有不同的基因表达特征。透明细胞乳头状肿瘤无TCEB1基因突变。组织病理学上,所有TCEB1突变肿瘤形态特征包括厚纤维肌束分隔肿瘤、单一透明细胞,常常有丰富的胞浆、肾透明细胞癌样腺泡区伴有折叠管状和局灶乳头状结构。出现丰富胞浆、无细胞核管腔极性分布并缺乏广泛的碳酸酐酶IX表达的杯状模式,可以与透明细胞乳头状癌鉴别。最后随访(中位数为48个月)中,无1例患者出现转移。总之,伴有TCEB1突变的肾细胞癌是一种反复出现热点突变的独特病变实体,显示特殊的染色体拷贝数量变化、通路的激活和独特的形态学特征。需要进一步临床随访,来确定与传统透明细胞肾细胞癌相比这些肿瘤是否更为惰性。
full text

我要评论

0条评论