PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers
PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers
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DOI：
10.1016/s0002-9440(10)64200-9
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发表时间：
2002-08-01
影响因子：
6
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Zhou, XP;Loukola, A;Eng, C
10q23.3上的PTEN编码双特异性磷酸酶，其负性调节磷酸肌醇-3-激酶/Akt途径并介导细胞周期停滞和凋亡。生殖系PTEN突变导致考登综合征和一系列不同的错构瘤-肿瘤综合征。遗传性非息肉病性结肠癌（HNPCC）综合征的特征是错配修复（MMR）基因的种系突变和组成肿瘤的微卫星不稳定性（MSI）。虽然结直肠癌和子宫内膜癌都是HNPCC中最常见的癌症，但只有子宫内膜癌被证明是Cowden综合征的次要组成部分。我们已经证明，PTEN的体细胞失活参与了散发性子宫内膜癌和HNPC相关子宫内膜癌，但具有不同的突变谱和与MSI的不同关系。在本研究中，我们试图确定结直肠癌（CRC）中PTEN突变、10 q23杂合性缺失、PTEN表达和MSI状态的关系。在11例HNPCC CRC、32例MSI+散发癌和39例MSI-肿瘤中，10 q23 -3杂合性缺失分别为0%、8%和19%。分别在18%（2/11）的HNPCC CRC和13%（4/32）的MSI+散发性肿瘤中发现了体细胞突变，但在MSI-癌症中未发现（P = 0.015）。所有体细胞突变均发生在PTEN的两个6（A）编码单核苷酸序列中，提示MMR缺陷的病因学作用。免疫组化分析显示31%（14/45）的HNPCC CRC和41%（9/22）的MSI+散发性肿瘤缺失或抑制PTEN表达。大约17%（23个中的4个）的MSI-CRC具有降低的PTEN表达，并且没有MSI-肿瘤具有PTEN表达的完全丧失。在具有免疫组织化学数据的携带移码体细胞突变的5个HNPCC或MSI+散发性CRC中，3个失去了所有PTEN表达，1个显示弱的PTEN表达水平，1个具有弱和中等表达水平的混合肿瘤细胞群。这些结果表明，HNPCC和散发性MSI+肿瘤中的PTEN移码突变是错配修复缺陷的结果。此外，MSI-CRC中的半合子缺失导致PTEN蛋白水平的丧失或降低并有助于肿瘤进展。最后，我们的数据还表明，表观遗传失活的PTEN，包括差异亚细胞区室化，发生在CRC。
PTEN on 10q23.3 encodes a dual-specificity phosphatase that negatively regulates the phosphoinositol-3-kinase/Akt pathway and mediates cell-cycle arrest and apoptosis. Germline PTEN mutations cause Cowden syndrome and a range of several different hamartoma-tumor syndromes. Hereditary nonpolyposis colon cancer (HNPCC) syndrome is characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. Although both colorectal carcinoma and endometrial carcinoma are the most frequent component cancers in HNPCC, only endometrial cancer has been shown to be a minor component of Cowden syndrome. We have demonstrated that somatic inactivation of PTEN is involved in both sporadic endometrial cancers and HNPCC-related endometrial cancers but with different mutational spectra and different relationships to MSI. In the current study, we sought to determine the relationship of PTEN mutation, 10q23 loss of heterozygosity, PTEN expression, and MSI status in colorectal cancers (CRCs). Among 11 HNPCC CRCs, 32 MSI+ sporadic cancers, and 39 MSI- tumors, loss of heterozygosity at 10q23-3 was found in 0%, 8%, and 19%. respectively. Somatic mutations were found in 18% (2 of 11) of the HNPCC CRCs and 13% (4 of 32) of the MSI+ sporadic tumors, but not in MSI- cancers (P = 0.015). All somatic mutations occurred in the two 6(A) coding mononucleotide tracts in PTEN, suggestive of the etiological role of the deficient MMR. Immunohistochemical analysis revealed 31% (14 of 45) of the HNPCC CRCs and 41% (9 of 22) of the MSI+ sporadic tumors with absent or depressed PTEN expression. Approximately 17% (4 of 23) of the MSI- CRCs had decreased PTEN expression, and no MSI- tumor had complete loss of PTEN expression. Among the five HNPCC or MSI+ sporadic CRCs carrying frameshift somatic mutations with immunohistochemistry data, three had lost all PTEN expression, one showed weak PTEN expression levels, and one had mixed tumor cell populations with weak and moderate expression levels. These results suggest that PTEN frameshift mutations in HNPCC and sporadic MSI+ tumors are a consequence of mismatch repair deficiency. Further, hemizygous deletions in MSI- CRCs lead to loss or reduction of PTEN protein levels and contribute to tumor progression. Finally, our data also suggest that epigenetic inactivation of PTEN, including differential subcellular compartmentalization, occurs in CRCs.