Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations

Nikaido, Mitsuhiro; Kakiuchi, Nobuyuki; Miyamoto, Shin’ichi; Hirano, Toshio; Takeuchi, Yasuhide; Funakoshi, Taro; Yokoyama, Akira; Ogasawara, Tatsuki; Yamamoto, Yoshihiro; Yamada, Atsushi; Setoyama, Takeshi; Shimizu, Takahiro; Kato, Yukari; Uose, Suguru; Sakurai, Takaki; Minamiguchi, Sachiko; Obama, Kazutaka; Sakai, Yoshiharu; Muto, Manabu; Chiba, Tsutomu; Ogawa, Seishi; Seno, Hiroshi

doi:10.1007/s10120-021-01191-8

Cited by 16 publications

(9 citation statements)

References 49 publications

(72 reference statements)

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“…Using exome analysis, we detected no significantly recurrent driver event in HP‐naïve DGCs aside from CDH1 mutation; this extremely stable genomic feature of the tumor may result in the indolent phenotype of HP‐naïve DGCs, as documented elsewhere [ 36 ]. Alternatively, HP‐naïve DGCs may be driven by epigenetic or noncoding drivers, which were unable to be identified in the current study.…”

Section: Discussionsupporting

confidence: 67%

“…In both studies, subjects were selected under comparably stringent criteria for HP infection status to those used in the current study. However, the detected frequency of driver mutations was very low in the former study [ 35 ], and HP‐exposed DGCs were not exome‐sequenced in the latter study [ 36 ]; these differences in study findings and design hinder us from making a direct comparison with our data.…”

Section: Discussionmentioning

confidence: 88%

“…Indeed, given that HP‐associated gastric cancer can arise even after the disappearance of HP infection [ 32 ], the absence of bacteria does not indicate a “never exposed” status [ 5 ], and thus the data from such cases are not suitable for studying the distinctive features of HP‐exposed and HP‐naïve gastric cancer genomes. Recently, two studies by Kiso et al and Nikaido et al were published, both of which focused on genomic alterations in HP‐naïve gastric cancer [ 35 , 36 ]. In both studies, subjects were selected under comparably stringent criteria for HP infection status to those used in the current study.…”

Section: Discussionmentioning

confidence: 99%

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Genomic features of Helicobacter pylori‐naïve diffuse‐type gastric cancer

Namikawa

Tanaka

Ota

et al. 2022

The Journal of Pathology

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Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-naïve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-naïve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HPexposed and 27 HP-naïve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-naïve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden ] and HP-naïve DGCs; 1.09 [0.38-3.68] per megabase; p = 0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p < 0.0001). CDH1 was mutated at similar frequencies in both groups, whereas the RHOA-ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p = 0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p < 0.0001), 7p (p = 0.0035), and 7q (p = 0.0354), and losses in 16q (p = 0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p < 0.0001) and CDX2 (p = 0.0002) and a lower expression of the gastric marker, MUC5AC (p = 0.0305) among HP-exposed DGCs. HP-naïve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-naïve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Genomic features of Helicobacter pylori‐naïve diffuse‐type gastric cancer

Namikawa

Tanaka

Ota

et al. 2022

The Journal of Pathology

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“…S1). As controls, we performed WES on 6 single normal glands in non-inflamed gastric mucosa and re-analyzed WES data of 13 single normal glands from 8 individuals, which were performed by the same methods as in the present study (29). The mean depth of targeted regions in single glands was 88.3× (54.5×-142.1×), while that in leukocytes was 89.5× (62.6×-141.3×) (Supplementary Table S5).…”

Section: Gastric Single Im Glands Highly Accumulate Mutations and Cnasmentioning

confidence: 99%

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization

et al. 2022

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Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; nineteen single glands in the non-inflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. Additionally, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and the Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired copy number aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable to those of IGC, contributing to field cancerization.

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“…In contrast to HpIGNs with enormous genomic alterations and epigenetic aberrations [31,32], HpNGNs primarily occur in cases with limited sporadic somatic mutations. Nakaido et al reported that Hp-naïve intramucosal SRCC showed the mutation of CDH1 gene in 67% (6/9) of cases, followed by TGFBR2, FAT4, and RNF43, but the number of mutations was similar to that in normal gastric glands [33].…”

Section: Discussionmentioning

confidence: 97%

Clinicopathologic differences of gastric neoplasms between Helicobacter pylori-infected and naïve patients

Kotani

Shibagaki

Hirahara

et al. 2022

Preprint

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Purpose The incidence of gastric neoplasms in Helicobacter pylori (Hp)-naïve patients has recently increased due to a remarkable decrease in the Hp–infected population in Japan. We investigated the clinicopathologic differences between patients with Hp-infected gastric neoplasms (HpIGNs) and those with Hp-naïve gastric neoplasms (HpNGNs) that have not been fully elucidated so far. Methods This retrospective study investigated 887 patients with 1010 gastric dysplasia or cancers who underwent endoscopic or surgical treatment for the recent decade. Clinical and neoplastic features were compared between HpIGN and HpNGN cases. Results HpNGNs accounted for 4.5% (45/1010) of all gastric neoplasm cases, but were found concentratedly in the latter five-years. Nine hundred sixty-five HpIGNs included 774 differentiated-type and 191 undifferentiated-type. Forty-five HpNGNs included 4 undifferentiated type, 5 fundic-gland type, 32 foveolar type, 3 intestinal type, and 1 other differentiated type. HpNGNs occurred in significantly younger patients (59.9 vs. 71.8 years, p<0.05), were found more frequently in the proximal compartment (p<0.05), and had smaller size (median 3.0 vs. 20.0 mm, p<0.05). Histologically, HpNGNs also showed a lower prevalence of invasive cancer (13.3% vs. 41.7%, p<0.05) and lymphovascular invasion (2.2% vs. 34.9%, p<0.05) as compared with HpIGN cases. Nearly all HpNGNs (44/45, 97.8%) were diagnosed in the early pathological stage, while 17.8% (172/965) of HpIGNs were diagnosed in an advanced stage (p=0.058). Conclusions HpNGN occurrence has recently been increasing along with an increase in Hp-naïve population and in knowledge about this type of tumor, though with a lower grade of biological malignancy regardless of histologic type.

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Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations

Cited by 16 publications

References 49 publications

Genomic features of Helicobacter pylori‐naïve diffuse‐type gastric cancer

Genomic features of Helicobacter pylori‐naïve diffuse‐type gastric cancer

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization

Clinicopathologic differences of gastric neoplasms between Helicobacter pylori-infected and naïve patients

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