Genetic analysis of a case of Helicobacter pylori-uninfected intramucosal gastric cancer in a family with hereditary diffuse gastric cancer

Funakoshi, Taro; Miyamoto, Shin’ichi; Kakiuchi, Nobuyuki; Nikaido, Mitsuhiro; Setoyama, Takeshi; Yokoyama, Akira; Horimatsu, Takahiro; Yamada, Atsushi; Torishima, Masako; Kosugi, Shinji; Yamada, Hidetaka; Sugimura, Haruhiko; Haga, Hironori; Sakai, Yoshiharu; Ogawa, Seishi; Seno, Hiroshi; Muto, Manabu; Chiba, Tsutomu

doi:10.1007/s10120-018-00912-w

Cited by 23 publications

(15 citation statements)

References 27 publications

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“…This suggests that, independently of the cancer setting (hereditary vs diffuse), or histological type (DGC vs IGC), GC developing in this CTNNA1 variant germline carrier presents a nonspecific combination of somatic events. By contrast, for the CDH1 germline mutated tumour, somatic mutations were described in TTN and CDH1 by Funakoshi et al [ 69 ], which are both specific DGC‐mutated genes (this study, Fig. 6 ); being CDH1 was also considered transversally mutated in SRCC and PCC‐NOS (Fig.…”

Section: Resultsmentioning

confidence: 57%

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Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

et al. 2021

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Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular, and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low-risk factors and hereditary GC is caused by inherited high-risk mutations, so far identified only for the diffuse histotype.DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC-specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC-related histological subtypes (Signet-Ring Cell Carcinoma (SRCC) and Poorly Cohesive Carcinoma not otherwise specified (PCC-NOS)). Indeed, DGC and DGC-related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC-NOS vs SRCC.In this systematic review, we revised the histological presentations, molecular classifications, and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC-NOS). We aimed at identifying histology-associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC-NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC-specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.

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Section: Resultsmentioning

confidence: 57%

“…We could only find two studies reporting the somatic mutational landscape of HDGC tumours [ 67 , 69 ]. The germline causative defect in one family affected CDH1 [ 69 ] and in the other family affected CTNNA1 [ 67 ].…”

Section: Resultsmentioning

confidence: 99%

Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

et al. 2021

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“…25 According to this classification, gastric cancers are classified as tumors positive for Epstein-Barr virus (EBV), microsatellite instability tumors, genomically stable tumors, and tumors with chromosomal instability according to the mechanism of carcinogenesis. With regard to HP-negative cancer, genetic disorders such as CDH1 are known in cases like hereditary diffuse gastric cancer 26 and GNAS in cases of gastric adenocarcinoma of the fundic gland type. 27 As for tumors with microsatellite instability, although they are often known to occur in female patients and arise from the antrum, 28 no decrease in the expression of MMR was observed in the lesions in this study.…”

Section: Discussionmentioning

confidence: 99%

Endoscopic and histological features of Helicobacter pylori‐negative differentiated gastric adenocarcinoma arising in the antrum

et al. 2021

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Background and Aim With the increasing prevalence of persons without Helicobacter pylori (HP) infection, cases of HP‐negative gastric cancer are increasing. Although rare, cases of differentiated adenocarcinoma of the antrum have been reported in HP‐negative patients. We collected cases with such lesions and investigated their endoscopic and histological features. Methods Of 1965 consecutive patients with early gastric cancer who underwent endoscopic resection between January 2009 and December 2017, we extracted 9 cases of HP‐negative differentiated adenocarcinoma located in the antrum (HPN‐DAA). The clinical data, endoscopic findings, and histopathological findings were reviewed. Results Of the nine patients with HPN‐DAA, seven were male, and the median age was 53.8 years. The tumor arose from the pyloric gland mucosa in all cases. According to the endoscopic findings, the lesions were flat‐elevated or depressed, mimicking varioliform gastritis. Magnifying endoscopy with narrow‐band imaging showed the absence of a clear demarcation line or an irregular microvessel/surface pattern. As for the histopathological findings, eight of the nine lesions were diagnosed as high‐grade dysplasia/intraepithelial neoplasia, while the remaining case was diagnosed as tubular adenocarcinoma with submucosal infiltration. The findings of immunohistochemistry confirmed that three cases were of the intestinal mucin phenotype and six were of the mixed gastric and intestinal mucin phenotype. Conclusion HPN‐DAA is a very rarely occurring cancer that had never been recognized earlier. They belong to the new category of HP‐negative cancers, and there seems to be a certain number of such cases.

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“…A possible reason for this might be because gastric carcinogenesis requires additional etiological hits that may be missing in the current lifestyles of east Asians. A recent case report from Japan investigated familial GC in two siblings; one sibling was infected with H. pylori and had an advanced GC, while the other was free from H. pylori and had an early-stage GC [ 101 ]. Although additional larger studies are necessary to draw a conclusion, this suggests that H. pylori infection plays a significantly additive role in gastric carcinogenesis, even in individuals with pathogenic germline CDH1 variants.…”

Section: Clinical Intervention For Hereditary Gcmentioning

confidence: 99%

Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations

Katoh

Ishikawa

2021

J Hum Genet

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The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming “H. pylori-negative era.”

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Genetic analysis of a case of Helicobacter pylori-uninfected intramucosal gastric cancer in a family with hereditary diffuse gastric cancer

Cited by 23 publications

References 27 publications

Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

Endoscopic and histological features of Helicobacter pylori‐negative differentiated gastric adenocarcinoma arising in the antrum

Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations

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