APC:T1556fs and STK11 mutations in duodenal adenomas and adenocarcinomas

Kojima, Yohei; Ohtsuka, Kouki; Ohnìshì, H.; Abe, Nobutsugu; Furuse, Junji; Watanabe, Takashi; Sugiyama, Masanori

doi:10.1007/s00595-018-1649-4

Cited by 10 publications

(25 citation statements)

References 25 publications

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“…Interestingly, we detected APC mutations (55%) more frequently in early non-ampullary duodenal lesions than did earlier studies in advanced lesions, which reported frequencies of 13-27% in SBAs or 8% in DAs [17,[20][21][22]. Kojima et al separately analyzed multiple components in non-ampullary duodenal lesions that exhibited different histological grades, and observed APC mutations more frequently in the adenoma (58%) than in the adenocarcinoma (25%) components [24]. The earlier observation that abnormal nuclear localization of β-catenin is more frequent in non-ampullary duodenal adenomas than in adenocarcinomas (84% versus 33%) may support these results [26].…”

contrasting

confidence: 51%

“…A customized panel, encompassing all exons for 75 cancer-related genes including those frequently mutated in SBAs [17][18][19][20][21]33,34], was created using the Ion Ampli-Seq Designer (Thermo Fisher Scientific) (supplementary material, Table S2). Genes whose mutations had been reported in duodenal adenomas were also included [24]. The assay design consisted of 3663 amplicons with an average length of 112 bp, covering 95.5% of the 366 kb target sequence.…”

Section: Targeted Amplicon Sequencing Analysismentioning

confidence: 99%

“…In addition, exome sequencing revealed potential driver genes, dysregulated oncogenic pathways, and targetable mutations in SBAs [18,19,21,22]. Still, the genetic alterations in early duodenal lesions are not fully understood, with only one earlier study analyzing mutations of 50 cancer-related genes in a limited number of samples [24].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies indicated that the genes recurrently mutated in SBAs are TP53 (41-58%), KRAS (27-54%), and APC (11-27%) [17][18][19][20][21][22]. An earlier study analyzed 50 hotspot mutations in cancer-related genes in 19 patients with non-ampullary duodenal adenomas and adenocarcinomas, and found prevalent mutations in KRAS (63%), APC (47%), and TP53 (37%) [24]. In the present study, we found mutations in APC (55%) and KRAS (13%); TP53 mutations were observed in only 5% of the samples.…”

mentioning

confidence: 99%

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Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Ota

Sawada

Tsuyama

et al. 2020

The Journal of Pathology

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The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal-and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear β-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis.

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contrasting

confidence: 51%

Section: Targeted Amplicon Sequencing Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Ota

Sawada

Tsuyama

et al. 2020

The Journal of Pathology

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“…A mutation cluster region (MCR) in exon 15 of APC 99, covering mainly the β-catenin-binding functional domain of APC, has been identified as a site with higher mutation rates, including gene deletions occurring in c.39273931delAAAGA and c.31833187delACAAA, and site mutations occurring in exon 15, c.1744G>A, or c.1744G>T 97, 100 (Figure 2A). Besides, according to a study by Kojima et al, APC and STK11 mutations found in duodenal adenomas/adenocarcinomas highlight the importance of proteins encoded by these genes in tumor development 75. Mutations in MUTYH have also been associated with FAP in special cases of recessive genetic FAP 101.…”

Section: Fap Susceptibility Genes and Mechanism Of Actionmentioning

confidence: 99%

Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer

Liu

Tan

2019

J. Cancer

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Colorectal cancer (CRC) is a common malignant tumor of the digestive system worldwide, associated with hereditary genetic features. CRC with a Mendelian genetic predisposition accounts for approximately 5-10% of total CRC cases, mainly caused by a single germline mutation of a CRC susceptibility gene. The main subtypes of hereditary CRC are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). With the rapid development of genetic testing methods, especially next-generation sequencing technology, multiple genes have now been confirmed to be pathogenic, including DNA repair or DNA mismatch repair genes such as APC, MLH1, and MSH2. Since familial CRC patients have poor clinical outcomes, timely clinical diagnosis and mutation screening of susceptibility genes will aid clinicians in establishing appropriate risk assessment and treatment interventions at a personal level. Here, we systematically summarize the susceptibility genes identified to date and the potential pathogenic mechanism of HNPCC and FAP development. Moreover, clinical recommendations for susceptibility gene screening, diagnosis, and treatment of HNPCC and FAP are discussed.

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Genomic profiling of intestinal/mixed‐type superficial non‐ampullary duodenal epithelial tumors

et al. 2021

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Background and Aim The mechanism underlying carcinogenesis and the genomic features of superficial non‐ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next‐generation sequencing (NGS). Methods Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer‐related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. Results The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low‐grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high‐grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusion We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations.

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APC:T1556fs and STK11 mutations in duodenal adenomas and adenocarcinomas

Cited by 10 publications

References 25 publications

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer

Genomic profiling of intestinal/mixed‐type superficial non‐ampullary duodenal epithelial tumors

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