RhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer

Yang, Hanna; Hong, Dong Ho; Cho, Soo Young; Park, Young Soo; Ko, Woo Ri; Kim, Ju Hee; Hur, Hoon; Lee, Jongkeun; Kim, Sujin; Kwon, Sun Young; Lee, Jae-Hyuk; Park, Do Youn; Song, Kyu Sang; Chang, Hee-Kyung; Ryu, Min‐Hee; Cho, Kye Soo; Kang, Jeong Won; Kook, Myeong–Cherl; Thiessen, Nina; He, An; Mungall, Andy J; Han, Sang‐Uk; Kim, Hark Kyun

doi:10.1038/s41467-018-06747-4

Cited by 27 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that the frequency of missense mutation was higher (67.8%) compared with that of non-missense mutation, and this result is similar to the previous analysis. A recent comprehensive genomic study demonstrated that RhoGAP domain-containing fusions or PPAPDC1A fusions, which are mostly somatic mutations, are common in GC of diffuse-type [38]. In addition, germline mutations in genes such as CTNNA1 were observed at a similar frequency as CDH1 germline mutation [39].…”

Section: Discussionmentioning

confidence: 99%

CDH1 mutations in gastric cancers are not influenced by family history

Choi¹,

Jang²,

Heo³

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

CDH1 mutations in gastric cancers are not influenced by family history

Choi¹,

Jang²,

Heo³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Skalova et al [29] proposed that claudin-1 and claudin-3 play a role in the response to chemotherapy in breast cancer. Yang et al [13] have suggested that patients with in-frame fusion genes containing the RhoGAP domain represent the aggressive subset of DGCs. Wang et al [30] have suggested that loss of E-cadherin is associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…First, the association between cell-adherens junction molecules was not con rmed by other methods. Recent studies have investigated these markers using several methods such as whole genome sequencing and RNA sequencing [11,13,14]. A previous study had found that the fusion of CLDN18.2 and ARHGAP26, which includes the RhoGAP domain, was observed frequently in mDGC [12].…”

Section: Discussionmentioning

confidence: 99%

“…A previous in vitro study reported that CLDN18-ARHGAP26 fusion-positive cell lines showed impaired barrier properties, reduced cell-cell adhesion, and augmented invasiveness [15]. Also, other previous studies suggested that CLDN18-ARHGAP26/6 or the RhoGAP domain-containing fusion protein was associated with poor prognosis of DGC [11,13].…”

Section: Introductionmentioning

confidence: 95%

“…Claudin-18 (CLDN18) is a member of the claudin family and is a component of tight junctions that regulate paracellular barrier functions. Several studies have suggested that DGC is associated with an inter-chromosomal translocation between CLDN18 and ARHGAP (gene encoding Rho GTPase-activating protein [RhoGAP], which contributes to the organization of the actin and microtubule cytoskeletons), which results in the generation of a RhoGAP domain-containing fusion protein in which the function of CLDN18 and RhoGAP is likely impaired [10][11][12][13][14]. A previous in vitro study reported that CLDN18-ARHGAP26 fusion-positive cell lines showed impaired barrier properties, reduced cell-cell adhesion, and augmented invasiveness [15].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Kim

Shin

Park

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Isoform 2 of the tight junction protein claudin-18 (CLDN18.2) is a potential target of gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC).Methods We evaluated CLDN18.2, RhoGAP, and E-cadherin expression by performing two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line, platinum-based chemotherapy between March 2015 and February 2017.Results CLDN18.2 and E-cadherin expression was significantly reduced in patients with peritoneal metastasis (PM) compared with those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), while it was significantly higher in patients who never exhibited PM from diagnosis to death than in those who did (p=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin were expressed at significantly higher levels in patients with bone metastasis than in those without it (p=0.010 and 0.001, respectively). We identified a positive correlation between the expression of CLDN18.2 and E-cadherin (p < 0.001), RhoGAP and CLDN18.2 (p=0.004), and RhoGAP and E-cadherin (p=0.001). CDLN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival.Conclusions CLDN18.2 expression was reduced in PM but significantly intact in bone metastasis. Furthermore, a positive correlation was identified between the expression of CLDN18.2 and other adherens junction molecules, which has clinical implications for mDGC and PM pathogenesis.

show abstract

Gene fusions in gastrointestinal tract cancers

Rahi

Olave

Fritchie

et al. 2022

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Fusion genes have been identified in a wide array of human neoplasms including hematologic and solid tumors, including gastrointestinal tract neoplasia. A fusion gene is the product of parts of two genes that are joined together following a deletion, translocation, or chromosomal inversion. Together with single nucleotide variants, insertions, deletions, and amplification, fusion genes represent one of the key genomic mechanisms for tumor development. Detecting fusions in the clinic is accomplished by a variety of techniques including break‐apart fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and next‐generation sequencing. Some recurrent gene fusions have been successfully targeted by small molecule or monoclonal antibody therapies (ie targeted therapies), while others are used as biomarkers for diagnostic and prognostic purposes. The purpose of this review article is to discuss the clinical utility of detection of gene fusions in carcinomas and neoplasms arising primarily in the digestive system.

show abstract

RhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer

Cited by 27 publications

References 53 publications

CDH1 mutations in gastric cancers are not influenced by family history

CDH1 mutations in gastric cancers are not influenced by family history

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Gene fusions in gastrointestinal tract cancers

Contact Info

Product

Resources

About