Gimm O, Chi H, Dahia P L, Perren A, Hinze R, Komminoth P, Dralle H, Reynolds P R, Eng C
Clinical Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
J Clin Endocrinol Metab. 2001 Apr;86(4):1801-5. doi: 10.1210/jcem.86.4.7419.
Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.
多种基因已被确定在滤泡性甲状腺肿瘤的发病机制中发挥作用。考登综合征是唯一已知的与滤泡性甲状腺腺瘤（FA）和癌（FTC）风险均增加相关的家族性综合征。肿瘤抑制基因PTEN的种系突变在高达80%的考登综合征患者中被发现，该基因编码一种双特异性磷酸酶，这表明PTEN在滤泡性甲状腺肿瘤的发病机制中发挥作用。尽管位于10q23.3的PTEN的体细胞内基因突变在滤泡性肿瘤中很少见，但10q22 - 24内标记物的杂合性缺失（LOH）在约25%的病例中出现。最近，另一种磷酸酶基因MINPP1已定位到10q23.3。MINPP1能够从肌醇磷酸底物上去除3 - 磷酸，这一功能与PTEN的功能重叠。由于与PTEN的这种功能重叠以及MINPP1在滤泡性甲状腺肿瘤中频繁发生LOH的区域的物理定位，我们认为它是一个可能促成滤泡性甲状腺肿瘤发病机制的优秀候选基因。我们分析了23例FA患者和15例FTC患者的肿瘤及相应正常组织的DNA，以检测MINPP1基因座的LOH和突变情况。在4例恶性肿瘤和3例良性肿瘤中发现了LOH。其中1例伴有LOH的FTC被发现存在体细胞c.122C > T或S41L突变。我们还发现了两个种系序列变异，c.809A > G（Q270R）和IVS3 + 34T > A。c.809A > G变异仅在1例FA患者中发现，而在FTC患者或正常对照中未发现。更有趣的是，IVS3 + 34T > A在约15%的FA病例和正常对照中发现，但在FTC患者中未发现。这些结果表明MINPP1在至少一部分恶性滤泡性甲状腺肿瘤的发病机制中发挥作用，并且MINPP1可能作为FTC的低外显率易感等位基因。
