影响多个癌症相关基因的基因突变和表观遗传修饰协同发生，驱动肿瘤发生。在多种癌症中，已在 SWIitch/蔗糖不可发酵复合体成员（包括其两个催化亚基 SMARCA4 和 SMARCA2）中发现了致病性变化。在癌症发展过程中，SMARCA4 或 SMARCA2 功能丧失的情况并不少见，然而，据报道，两者同时丧失会导致合成致死，因此是出乎意料的。 SMARCA4 和 SMARCA2 的共同缺陷是早发性卵巢癌（卵巢小细胞癌，高钙血症型）的一个典型特征。两种催化亚基的缺失也见于其他罕见的未分化肿瘤，包括胸部 SMARCA4 缺陷型未分化肿瘤、恶性横纹肌样瘤和去分化或未分化癌，主要起源于肺癌、胃肠道和子宫内膜。这篇综述通过共同的临床和分子特征的讨论，首次对同时存在 SMARCA4 和 SMARCA2 缺失的癌症进行了广泛的描述。此外，我们还讨论了触发催化活性丧失的机制、因此导致功能失调的细胞过程，以及最后可能选择性针对这些癌症的当前候选治疗方案。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Genetic mutations and epigenetic modifications affecting multiple cancer-related genes occur synergistically to drive tumorigenesis. Across a wide spectrum of cancers, pathogenic changes have been identified in members of the SWItch/Sucrose Non-Fermentable complex including its two catalytic subunits, SMARCA4 and SMARCA2. During cancer development, it is not uncommon to lose the function of either SMARCA4 or SMARCA2, however, loss of both together has been reported to be synthetic lethal and therefore unexpected. Co-deficiency of SMARCA4 and SMARCA2 occurs as a pathognomonic feature of the early-onset ovarian cancer Small-cell carcinoma of the ovary, hypercalcemic type. The loss of both catalytic subunits is also described in other rare undifferentiated neoplasms including Thoracic SMARCA4-deficient undifferentiated tumors, Malignant rhabdoid tumors and dedifferentiated or undifferentiated carcinomas, predominantly of lung, gastrointestinal, and endometrial origin. This review provides the first extensive characterization of cancers with concurrent SMARCA4 and SMARCA2 loss through the discussion of shared clinical and molecular features. Further, we discuss the mechanisms triggering the loss of catalytic activity, the cellular processes that are dysfunctional as a consequence, and finally, current therapeutic candidates which may selectively target these cancers.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.