Centro 基因型优先方法确定CDH1种系变体与癌症表型的关联：欧洲遗传性肿瘤风险综合征参考网络的多中心研究

SCI 16 December 2022

Centro Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes

（Lancet Oncol IF 54.433）

José Garcia-Pelaez, Rita Barbosa-Matos*, Silvana Lobo*, Alexandre Dias*, Luzia Garrido, Sérgio Castedo, Sónia Sousa, Hugo Pinheiro,

Liliana Sousa, Rita Monteiro, Joaquin J Maqueda, Susana Fernandes, Fátima Carneiro, Nádia Pinto, Carolina Lemos, Carla Pinto, Manuel R Teixeira, Stefan Aretz, Svetlana Bajalica-Lagercrantz, Judith Balmaña, Ana Blatnik, Patrick R Benusiglio, Maud Blanluet, Vicent Bours, Hilde Brems,

Joan Brunet, Daniele Calistri, Gabriel Capellá, Sergio Carrera, Chrystelle Colas, Karin Dahan, Robin de Putter, Camille Desseignés,

Elena Domínguez-Garrido, Conceição Egas, D Gareth Evans, Damien Feret, Eleanor Fewings, Rebecca C Fitzgerald, Florence Coulet,

María Garcia-Barcina, Maurizio Genuardi, Lisa Golmard, Karl Hackmann, Helen Hanson, Elke Holinski-Feder, Robert Hüneburg, Mateja Krajc, Kristina Lagerstedt-Robinson, Conxi Lázaro, Marjolijn J L Ligtenberg, Cristina Martínez-Bouzas, Sonia Merino, Geneviève Michils,

Srdjan Novaković, Ana Patiño-García, Guglielmina Nadia Ranzani, Evelin Schröck, Inês Silva, Catarina Silveira, José L Soto, Isabel Spier,

Verena Steinke-Lange, Gianluca Tedaldi, María-Isabel Tejada, Emma R Woodward, Marc Tischkowitz, Nicoline Hoogerbrugge, Carla Oliveira

Background 背景

Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype– phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing.

CDH1的截断致病变体或可能致病的变体导致遗传性弥漫性胃癌（HDGC），这是一种肿瘤风险综合征，使携带者易患弥漫性胃癌和小叶性乳腺癌。罕见的CDH1错义变体通常被归类为意义不明的变体。我们对携带罕见CDH1变体的家庭进行了基因型-表型分析，比较致病性或可能致病性变体（PV/LPV；共同分析）或意义不明的错义变体携带者的癌症谱，评估PV/LPV携带者家庭中患小叶乳腺癌的频率，并测试小叶乳腺癌扩展标准在CDH1检测中的表现。

Methods 方法

This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student’s t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test.

这项基因型优先的研究使用了来自欧洲肿瘤风险综合征参考网络（ERN GENTURIS）10个成员国的29家机构的854名398个罕见CDH1变异的携带者和1021名亲属的回顾性诊断和临床数据，不考虑HDGC临床标准。数据收集时间为2018年10月1日至2022年9月20日。根据美国医学遗传学学院和分子病理学协会CDH1指南（第二版），变体按分子类型和临床可操作性分类。家属按是否符合2015年和2020年HDGC临床标准进行分类。通过学生t检验、Kruskal-Wallis、χ2和多变量逻辑回归模型分析基因型与表型的关联。用等值检验和尤登指数评估HDGC临床标准集的性能，用Z检验比较接受者操作特征曲线下的面积。

Findings 研究结果

From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004).

在1971个表型中（由854名原告和1021名1-93岁的亲属提供），460名有胃癌和乳腺癌组织学资料。854个家庭中有176个（21%）发生CDH1截断型PV/LPVs，169个（20%）家庭发生意义不明的错义变体。多变量逻辑回归比较了携带PV/LPVs或意义不明的错义变体的家庭中出现的表型，显示小叶乳腺癌与PV/LPVs的存在有最大的正相关（几率12-39[95%CI 2-66-57-74]，p=0-0014），其次是弥漫性胃癌（8-00[2-18-29-39]，p=0-0017）和胃癌（7-81[2-03-29-96]，p=0-0027）。176个携带PV/LPV的家庭中，136个（77%）符合2015年HDGC标准。其余40个（23%）家庭，不符合2015年的标准，11个符合2020年的HDGC标准，18个仅有小叶乳腺癌或小叶乳腺癌和胃癌，但不符合2020年的标准。虽然176个PV/LPV携带者家族中有12个（7%）只患有小叶乳腺癌，但没有发现特定的CDH1变异使个体特别容易患小叶乳腺癌。增加了三个新的以小叶乳腺癌为中心的标准，提高了测试的灵敏度，同时保留了高特异性。与2020年的标准相比，在满足小叶乳腺癌扩展标准的患者中发现CDH1 PV/LPV的概率明显增加（AUC 0-92 vs 0-88；Z score 3-54；P=0-0004）。

Interpretation 解读

CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria.

CDH1 PV/LPVs与HDGC相关表型（小叶乳腺癌、弥漫性胃癌和胃癌）呈正相关，而对于意义不明的CDH1错义变异，没有发现与这些表型呈正相关的证据。CDH1 PV/LPVs经常发生在不符合2020年HDGC标准的小叶乳腺癌家族中，支持扩大以小叶乳腺癌为中心的标准。