APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum

Ishizu, Kenichi; Hashimoto, Taiki; Naka, Tomoaki; Yatabe, Yasushi; Kojima, Masaru; Kuwata, Takeshi; Nonaka, Satoru; Oda, Ichiro; Esaki, Minoru; Kudo, Masashi; Gotohda, Naoto; Yoshida, Teruhiko; Yoshikawa, Takaki; Sekine, Shigeki

doi:10.1007/s00535-021-01823-x

Cited by 8 publications

(6 citation statements)

References 50 publications

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“…MSI-H is associated with aggressive tumor behavior in gastric and colorectal cancers and is a poor prognostic factor of colorectal cancer ( 28 , 29 ). Concerning duodenal tumors, several studies showed that genetic mutations (e.g., GNAS , KRAS ) in gastric-type tumors of the stomach were also found in gastric-type tumors of the duodenum ( 30 , 31 ). Particularly, Ishizu et al ( 31 ) reported a low mutation rate of the APC gene in nonpapillary duodenal adenocarcinomas, whereas the mutation rate was high in intestinal-type adenomas, suggesting that common intestinal-type adenomas are not likely major precursors of adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Non–Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study

Uema,

Hayashi,

Komori

et al. 2023

Clin Transl Gastroenterol

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Introduction: We aimed to evaluate the natural course of sporadic non-ampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. Methods: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. Results: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, five lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex (P=0.046), initial lesion size ≥10 mm (P=0.044), and non-pure intestinal phenotype (P=0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm (P<0.001), erythematous lesion (P=0.002), high-grade adenoma (P=0.002), Ki67 negative (P=0.007), and non-pure intestinal phenotype (P=0.001) were risk factors for tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm (P=0.010) and non-pure intestinal phenotype (P=0.046) were independent and significant risk factors for tumor enlargement. Conclusions: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors for cancer progression and tumor enlargement in SNDA cases. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

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Section: Discussionmentioning

confidence: 99%

Non–Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study

Uema,

Hayashi,

Komori

et al. 2023

Clin Transl Gastroenterol

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“…Genetic variation in GNAS is associated with birth weight [11,148]. Mutations in the GNAS gene are frequently observed in a variety of malignant, premalignant, and benign tumors and in tumor-derived organoids and patient-derived xenografts [19,[149][150][151][152][153][154]. This gene has been reported to play an oncogenic role in SCLC.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue specificity of their imprinting, in addition to variation in gene expression among tissues regulated by mechanisms other than imprinting, underscores the importance of future analyses of associations of allelic dosage, parent-specific allelic expression, and novel types of omics data [3] with drug response, which would need to be conducted in separate tumor categories with large sample sizes. An additional analysis of the mutation status of the imprinted genes in tumors would add further depth to the understanding of their influence on drug response, since protein-changing mutations in many imprinted genes including those genes which were associated with drug response in our study, e.g., NLRP2, CDKN1C, and GNAS, commonly occur in patients with imprinted disorders and/or cancer [1,129,131,[149][150][151][152][153][154]156].…”

Section: Discussionmentioning

confidence: 99%

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

et al. 2022

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Background Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment. Results We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes. Conclusions Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy.

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“…15 Only a few studies have been reported that classified SBA into gastric and intestinal types and that examined clinicopathologic differences using immunostaining for phenotype markers. [16][17][18][19] Although immunostaining for CK7/20, CD10, CDX2, and various mucins has already been investigated on their own in a number of SBA studies, there has been no investigation to date that has brought all of these markers under one study for comprehensive analyses. 16,[20][21][22][23][24][25][26][27] More studies are warranted to evaluate these issues through comprehensive analyses of immunohistochemical phenotype markers.…”

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confidence: 99%

“…Our own studies have shown that mutations of APC and CTNNB1 have an inverse relationship with gastric-type markers, but it remains to be determined whether gastric-type and intestinal-type SBAs have different clinicopathologic characteristics 15 . Only a few studies have been reported that classified SBA into gastric and intestinal types and that examined clinicopathologic differences using immunostaining for phenotype markers 16–19 . Although immunostaining for CK7/20, CD10, CDX2, and various mucins has already been investigated on their own in a number of SBA studies, there has been no investigation to date that has brought all of these markers under one study for comprehensive analyses 16,20–27 .…”

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confidence: 99%

Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma

Hoshimoto,

Tatsuguchi,

Yamada

et al. 2023

American Journal of Surgical Pathology

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Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.

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APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum

Cited by 8 publications

References 50 publications

Non–Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study

Non–Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma

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