Specific Mutations in the β-Catenin Gene (CTNNB1) Correlate with Local Recurrence in Sporadic Desmoid Tumors
Specific Mutations in the β-Catenin Gene (CTNNB1) Correlate with Local Recurrence in Sporadic Desmoid Tumors
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DOI：
10.2353/ajpath.2008.080475
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Lev, Dina
中科院分区：
文献类型：
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作者：
Lazar, Alexander J. F.;Tuvin, Daniel;Lev, Dina
韧带纤维瘤病是一种罕见的非转移性肿瘤，具有局部侵袭性和无休止复发的特点。韧带样变复发的分子决定因素仍不清楚。虽然CTNNB1(编码β-连环素的基因)突变的发生率尚不确定，但在散发性韧带样变中普遍发现了β-连环素的失控。因此，我们评估了CTNNB1突变在一大群散发性韧带样瘤中的流行率，并检查了突变类型是否与韧带样瘤的结局相关。硬纤维样标本(来自160名患者的195个肿瘤，1985年至2005年)和对照真皮瘢痕被组装成一个临床数据关联的组织微阵列。对138个散发性硬纤维样亚群进行CTNNB1基因分型。免疫组织化学评分按标准进行，数据分析采用Kaplan-Meier等指标法。在138例韧带样变中，有117例(85%)发现CTNNB1突变。在CTNNB1外显子3的两个密码子中发现了三个离散突变：41A(59%)、45F(33%)和45P(8%，因罕见而排除在进一步分析之外)。45F突变的韧带样癌的五年无复发生存率(23%，P<；0.0001)明显低于41a(57%)或非突变的肿瘤(65%)。在98%的标本中观察到核β-连环蛋白的表达，其表达强度与硬纤维瘤复发的发生率呈负相关(P<；0.01)。综上所述，CTNNB1突变在韧带样瘤中非常常见。此外，携带CTNNB1(45F)突变的患者特别有可能复发，因此可能特别受益于辅助治疗方法。(Am J Pathol2008,17315181527；DOI：10.2353/ajpath.2008.080475)
Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. beta-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encodmig beta-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%), 45F (33%), and 45P (8%, excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23%, P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. (Am J Pathol 2008, 173-1518-1527; DOI: 10.2353/ajpath.2008.080475)