Germline CDH1 G212E Missense Variant: Combining Clinical, In Vitro and In Vivo Strategies to Unravel Disease Burden.
Germline CDH1 G212E Missense Variant: Combining Clinical, In Vitro and In Vivo Strategies to Unravel Disease Burden.
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DOI：
10.3390/cancers13174359
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发表时间：
2021-08-28
期刊：
影响因子：
5.2
通讯作者：
Urioste M
中科院分区：
文献类型：
--
作者：
Figueiredo J;Mercadillo F;Melo S;Barroso A;Gonçalves M;Díaz-Tasende J;Carneiro P;Robles L;Colina F;Ibarrola C;Perea J;Morais-de-Sá E;Seruca R;Urioste M
遗传性弥漫性胃癌 (HDGC) 是一种与 CDH1 种系突变相关的遗传性癌症综合征。由于多基因组检测，CDH1 遗传变异的检测量不断增加，这给临床带来了严峻的挑战，并敦促开发有效的分类策略。在这项研究中，我们描述了在一个受弥漫性胃癌严重影响的大家族中新的 CDH1 G212E 变异的鉴定。通过全面的表征流程，我们提供了这种基因改变的破坏性的证据，从而影响患者管理和家庭筛查。 E-钙粘蛋白由 CDH1 编码，是上皮稳态的重要分子，其缺失或异常表达会导致细胞间粘附紊乱、细胞侵袭和转移增加。 CDH1 种系突变携带者患弥漫性胃癌和小叶乳腺癌的风险很高，与癌症综合征遗传性弥漫性胃癌 (HDGC) 相关。癌症检测试剂盒的普及导致越来越多的“偶然”CDH1 遗传变异被识别出来，这给临床带来了严峻的挑战。这引发了深入的研究，旨在对变异进行准确分类并随后验证其临床相关性。本研究探讨了一种新的 CDH1 变体 G212E 的重要性，该变体是在一个异常大的谱系中发现的，显示出弥漫性胃癌的强烈聚集。我们进行了一个全面的研究，包括家庭数据、计算机预测、体外测定和体内策略，验证了这种基因改变引起的有害表型。特别是，我们证明 G212E 变异会影响 E-钙粘蛋白的稳定性和定位以及粘附和抗侵袭功能，从而引发上皮破坏和解体。我们的研究结果说明了有效变异分类和患者管理的补充方法的临床意义。
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome associated with CDH1 germline mutations. The increasing detection of CDH1 genetic variants due to multigene panel testing poses a serious clinical challenge and urges the development of effective classification strategies. In this study, we describe the identification of the novel CDH1 G212E variant in a large family strongly affected by diffuse gastric cancer. Through a comprehensive characterization pipeline, we provide evidence of the damaging nature of this genetic alteration, thus impacting patient management and family screening. E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metastasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.
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影响因子：
64.8
作者：
Findlay GM;Daza RM;Martin B;Zhang MD;Leith AP;Gasperini M;Janizek JD;Huang X;Starita LM;Shendure J
通讯作者：
Shendure J
影响因子：
24.5
作者：
Kim, HC;Wheeler, JMD;Bodmer, WF
通讯作者：
Bodmer, WF
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
4.6
作者：
Figueiredo J;Rodrigues I;Ribeiro J;Fernandes MS;Melo S;Sousa B;Paredes J;Seruca R;Sanches JM
通讯作者：
Sanches JM
影响因子：
9.8
作者：
Favalli, Valentina;Tini, Giulia;Mazzarella, Luca
通讯作者：
Mazzarella, Luca