The majority of β-catenin mutations in colorectal cancer is homozygous.
The majority of β-catenin mutations in colorectal cancer is homozygous.
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DOI：
10.1186/s12885-020-07537-2
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发表时间：
2020-10-28
期刊：
影响因子：
3.8
通讯作者：
Bläker H
中科院分区：
文献类型：
--
作者：
Arnold A;Tronser M;Sers C;Ahadova A;Endris V;Mamlouk S;Horst D;Möbs M;Bischoff P;Kloor M;Bläker H
β-连环蛋白激活在大肠肿瘤发生中起着至关重要的作用，但除了林奇综合征（LS）之外，β-连环蛋白基因（CTNNB1）稳定突变在结直肠癌（CRC）中很少见。先前的动物研究为这一观察结果提供了解释。他们表明，只有当 CTNNB1 纯合突变或膜 β-连环蛋白结合受到 E-钙粘蛋白单倍体不足阻碍时，CTNNB1 突变才会诱导结肠中的转化。我们感兴趣的是，这些机制是否也存在于人类 CTNNB1 突变的 CRC 中。在 869 个 CRC 中，有 27 例发现稳定 CTNNB1 突变。在 74% 的 CTNNB1 突变 CRC 中检测到同源或半合子 CTNNB1 突变（13 个微卫星不稳定 (MSI-H)，7 个微卫星稳定 (MSS)），但仅在 3% (1/33) 的结肠外 CTNNB1 突变癌症中检测到。与 MSS CRC 相比，MSI-H CRC 中密码子 41 或 45 处的 CTNNB1 突变被高度选择。在所检查的三种CRC细胞系中，在不具有或具有杂合CTNNB1突变的细胞系（DLD1和HCT116）中，β-连环蛋白和E-钙粘蛋白表达相似，而在具有纯合CTNNB1突变的细胞系（LS180）中发现E-钙粘蛋白表达降低且细胞质中β-连环蛋白积聚。在 60% 的研究癌症中发现人类 MSI-H CRC 组织中 E-钙粘蛋白的表达降低，但未发现与 CTNNB1 突变状态相关。总之，这项研究表明，与结肠外癌症相比，CRC 中稳定的 CTNNB1 突变通常是同源或半合子，表明与结肠外位点相比，结肠中的转化需要更高的 β-连环蛋白稳定阈值。此外，我们发现 MSI-H 和 MSS CRC 的 CTNNB1 中存在不同的突变热点，这表明根据肿瘤发生的分子途径，对 β-连环蛋白稳定性有不同的影响。 CRC 中 E-钙粘蛋白表达的减少可能进一步导致转录活性 β-连环蛋白水平升高，但它与 CTNNB1 突变状态没有直接关系。本文随附的补充信息为 10.1186/s12885-020-07537-2。
β-catenin activation plays a crucial role for tumourigenesis in the large intestine but except for Lynch syndrome (LS) associated cancers stabilizing mutations of β-catenin gene (CTNNB1) are rare in colorectal cancer (CRC). Previous animal studies provide an explanation for this observation. They showed that CTNNB1 mutations induced transformation in the colon only when CTNNB1 was homozygously mutated or when membranous β-catenin binding was hampered by E-cadherin haploinsufficiency. We were interested, if these mechanisms are also found in human CTNNB1 mutated CRCs. Among 869 CRCs stabilizing CTNNB1 mutations were found in 27 cases. Homo- or hemizygous CTNNB1 mutations were detected in 74% of CTNNB1 mutated CRCs (13 microsatellite instabile (MSI-H), 7 microsatellite stabile (MSS)) but only in 3% (1/33) of extracolonic CTNNB1 mutated cancers. In contrast to MSS CRC, CTNNB1 mutations at codon 41 or 45 were highly selected in MSI-H CRC. Of the examined three CRC cell lines, β-catenin and E-cadherin expression was similar in cell lines without or with hetereozygous CTNNB1 mutations (DLD1 and HCT116), while a reduced E-cadherin expression combined with cytoplasmic accumulation of β-catenin was found in a cell line with homozygous CTNNB1 mutation (LS180). Reduced expression of E-cadherin in human MSI-H CRC tissue was identified in 60% of investigated cancers, but no association with the CTNNB1 mutational status was found. In conclusion, this study shows that in contrast to extracolonic cancers stabilizing CTNNB1 mutations in CRC are commonly homo- or hemizygous indicating a higher threshold of β-catenin stabilization to be required for transformation in the colon as compared to extracolonic sites. Moreover, we found different mutational hotspots in CTNNB1 for MSI-H and MSS CRCs suggesting a selection of different effects on β-catenin stabilization according to the molecular pathway of tumourigenesis. Reduced E-cadherin expression in CRC may further contribute to higher levels of transcriptionally active β-catenin, but it is not directly linked to the CTNNB1 mutational status. Supplementary information accompanies this paper at 10.1186/s12885-020-07537-2.
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DOI：
10.15252/embj.201591739
发表时间：
2015-09-14
期刊：
The EMBO journal
影响因子：
--
作者：
Huels DJ;Ridgway RA;Radulescu S;Leushacke M;Campbell AD;Biswas S;Leedham S;Serra S;Chetty R;Moreaux G;Parry L;Matthews J;Song F;Hedley A;Kalna G;Ceteci F;Reed KR;Meniel VS;Maguire A;Doyle B;Söderberg O;Barker N;Watson A;Larue L;Clarke AR;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
2
作者：
Kim, Jin Young;Park, Geumi;Chun, Kyung-Soo
通讯作者：
Chun, Kyung-Soo
影响因子：
9.7
作者：
Akiyama, Y;Nagasaki, H;Yuasa, Y
通讯作者：
Yuasa, Y
影响因子：
3.3
作者：
FUJIMORI, T;TAKEICHI, M
通讯作者：
TAKEICHI, M
影响因子：
13.5
作者：
Rebouissou, Sandra;Franconi, Andrea;Zucman-Rossi, Jessica
通讯作者：
Zucman-Rossi, Jessica