Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer

Shu, Yang; Zhang, Weihan; Hou, Qing; Zhao, Lin-Yong; Zhang, Shouyue; Zhou, Jian‐Kang; Xiao, Song; Zhang, Yan; Jiang, Dan; Chen, Xinzu; Wang, Peiqi; Xia, Xuyang; Liao, Fei; Yin, Dandan; Zhou, Xueyan; Zhang, Duyu; Yin, Senlin; Yang, Kun; Liu, Jianping; Fu, Leilei; Zhang, Lan; Wang, Yuelan; Zhang, Junlong; An, Yunfei; Cheng, Hua; Zheng, Bin; Sun, Hongye; Zhao, Yinglan; Wang, Yongsheng; Xie, Dan; Ouyang, Liang; Wang, Ping; Zhang, Wei; Meng, Qingcai; Fu, Xianghui; Dai, Lunzhi; He, Gu; Yang, Huiling; Cheng, Wei; Yang, Li; Liu, Bo; Liu, Weimin; Dong, Biao; Zhou, Zong‐Guang; Wei, Yuquan; Peng, Yong; Xu, Hong‐Xi; Hu, Jian‐Kun

doi:10.1038/s41467-018-04907-0

Cited by 115 publications

(115 citation statements)

References 45 publications

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“…Gastric cancer is one of the most common malignant tumors of the digestive tract, and currently accounts for 8.2% of all new cancer cases worldwide . Adenocarcinomas represent the majority of gastric cancers, while signet ring cell carcinoma (SRCC) is a poorly differentiated subtype of gastric carcinoma with unique clinical characteristics and poor survival rates . Previous studies indicated that gastric SRCC has different risk factors compared to non‐SRCC gastric cancer (NOS) types, including older age, female gender, smoking, obesity and American Joint Committee on Cancer (AJCC) IV stage .…”

Section: Introductionmentioning

confidence: 99%

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

et al. 2019

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Background Stage IV gastric signet ring cell carcinoma (SRCC) is a type of malignant gastric cancer (GC) with poorer survival compared to metastatic non‐SRCC gastric cancer (NOS). However, chemotherapy alone was unable to maintain long‐term survival. This study aimed to evaluate survival benefit of palliative gastrectomy plus chemotherapy (PG+C) for metastatic gastric SRCC. Methods We obtained data on gastric cancer patients between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Statistical methods included χ2 tests, Kaplan‐Meier curves, COX models, propensity score matching (PSM) and subgroup analysis. Results Among 27 240 gastric cancer patients included, 4638 (17.03%) were SRCC patients. The proportion of patients with younger age, female gender, poorly differentiated grade and M1 stage was higher in SRCC than in NOS (P < .001). Multivariate analysis revealed that multiple metastatic sites (HR = 1.39, 95% CI: 1.14‐1.69, P = .001) was associated with increased mortality risk in metastatic SRCC. Median survival time was improved in metastatic SRCC receiving PG+C compared to PG/C alone (13 vs 7 months, P < .001). Notably, in subgroup analysis, 13 of 17 groups of metastatic SRCC patients with PG+C had prolonged overall survival compared to chemotherapy alone, especially for those with only one metastatic site (HR = 0.61, 95% CI: 0.51‐0.73, P < .001). Conclusions Our results suggested that there exists at least a selective group of stage IV gastric SRCC patients, who could benefit from palliative gastrectomy followed by chemotherapy compared to chemotherapy alone. Further prospective trials are needed to support our conclusion.

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Section: Introductionmentioning

confidence: 99%

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

et al. 2019

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“…of GC cases [16][17][18][19][20][21][22] and are highly prevalent in sporadic EODGC (53.2% of cases). Somatic CDH1 mutation has also been suggested as a poor prognostic marker in diffuse-type GC [17,22,23].…”

Section: Discussionmentioning

confidence: 99%

“…While this strategy has resulted in significant increases in identification of individuals at risk, it has also led to clinical conundrums regarding management of nonsyndromic carriers of an unexpected or unanticipated genetic mutation [14], such as patients with CDH1 mutation [15]. With NGS, somatic mutations of CDH1 are found in 9%~36% of GC cases [16][17][18][19][20][21][22] and are highly prevalent in sporadic early-onset diffuse-type GC (EODGC) (53.2% of cases) [17]. Somatic mutations of CDH1 have been suggested as a poor prognostic marker in diffuse-type GC [22,23].…”

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confidence: 99%

CDH1 mutations in gastric cancers are not influenced by family history

Choi¹,

Jang²,

Heo³

et al. 2020

Preprint

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Background: CDH1 mutation is the most frequent genetic alteration in hereditary diffuse gastric cancer (GC) and early onset diffuse GC patients. However, the incidence of CDH1 mutations in sporadic GC with or without family history has not been studied. Methods: This retrospective study includes a total of 993 Korean patients with primary advanced GC who underwent surgery and received palliative chemotherapy. Targeted deep sequencing was performed in all cases and family history of GC was searched with survival analysis. Results: We found CDH1 alterations in 146 of 993 patients (14.7%) and 8 were germline (0.8%). Out of 146 patients with CDH1 mutations, 25 (17.1%) had a family history of GC in one of their first relatives, and 12 patients (8.2%) were diagnosed with familial GC (FGC). All cases with FGC were diffuse type by Lauren classification, and only one harbored a previously reported germline mutation of CDH1 (c.2638G>A) and the remaining 11 harbored known somatic CDH1 mutations. Among all patients with CDH1 mutation, there was no significant survival difference between patients with family history or FGC. In the 847 patients without CDH1 mutation, 189 (22.3 %) had a family history of GC and 92 patients (10.9%) were FGC. CDH1 mutations were more frequent in patients with early onset (<45 years) GC (45.5%) compared with patients with late onset GC (10.9%) (p = 0.001), but were not significantly associated with the family history of GC (p > 0.05). Conclusions: CDH1 mutations are mostly somatic and typically are not associated with family history.

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“…In a systematic investigation conducted in 1868 Chinese GC patients, whole‐genome sequencing on 32 pairs of signet‐ring cell carcinoma (SRCC) samples, CLDN18‐ARHGAP26/6 fusion was frequently identified (25%) . CLDN18‐ARHGAP26/6 fusion was associated with signet‐ring cell content, age at diagnosis, female/male ratio, and TNM stage, worse survival outcomes, and no benefit from oxaliplatin/fluoropyrimidine‐based chemotherapy.…”

Section: Gastric Cancer: Treatmentmentioning

confidence: 99%

Review: Gastric cancer—Clinical aspects

et al. 2019

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Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non‐cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16‐year endoscopy‐based follow‐up eradication trial, patients with incomplete‐type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first‐line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second‐line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18‐ARHGAP26/6 fusion was associated with signet‐ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine‐based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future.

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Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer

Cited by 115 publications

References 45 publications

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

Survival benefit of palliative gastrectomy followed by chemotherapy in stage IV gastric signet ring cell carcinoma patients: A large population‐based study

CDH1 mutations in gastric cancers are not influenced by family history

Review: Gastric cancer—Clinical aspects

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