SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling

IF 9.1 1区 医学 Q1 ONCOLOGY
Natisha R. Field , Kristie-Ann Dickson , Najah T. Nassif , Deborah J. Marsh
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引用次数: 0

Abstract

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.
SMARCA4和SMARCA2共同缺陷:一种不常见的分子特征,可定义与染色质重塑缺陷有关的罕见、侵袭性和未分化恶性肿瘤亚群。
影响多个癌症相关基因的基因突变和表观遗传修饰会协同驱动肿瘤发生。在多种癌症中,SWItch/蔗糖不发酵复合体成员(包括其两个催化亚基 SMARCA4 和 SMARCA2)的致病性变化已被确定。在癌症发展过程中,SMARCA4 或 SMARCA2 功能丧失的情况并不少见,但据报道,同时丧失这两种功能会导致合成性死亡,因此是意想不到的。SMARCA4和SMARCA2同时缺失是早发卵巢癌卵巢小细胞癌(高钙血症型)的病理特征。在其他罕见的未分化肿瘤中也发现了两种催化亚基的缺失,包括胸腔 SMARCA4 缺失型未分化肿瘤、恶性横纹肌瘤以及主要源于肺、胃肠道和子宫内膜的去分化或未分化癌。本综述通过讨论共同的临床和分子特征,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,我们还讨论了引发催化活性丧失的机制、因此而功能失调的细胞过程,最后还讨论了目前可能选择性地针对这些癌症的候选疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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