CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

Sun, Long; Guzzetta, Angela A.; Fu, Tao; Chen, Jin‐Ming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B.; Iacobuzio‐Donahue, Christine A.; Wolfgang, Christopher Cl; Ahuja, Nita

doi:10.4161/epi.28082

Cited by 7 publications

(8 citation statements)

References 40 publications

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“…If specific endoscopic findings for lesions with concurrent methylation are determined, detailed endoscopic assessment could contribute to the prediction of premalignant lesions, as was previously reported for colorectal serrated lesions [45]. MLH1 methylation has been reported in 12% of nonampullary adenomas [16] as well as in 14% [15] or 25% [14] of DAs. MSI has also been reported in 20% [15] or 33% [17] of DAs, where it is reportedly associated with MLH1 methylation [15].…”

mentioning

confidence: 74%

“…MLH1 methylation has been reported in 12% of non‐ampullary adenomas [16] as well as in 14% [15] or 25% [14] of DAs. MSI has also been reported in 20% [15] or 33% [17] of DAs, where it is reportedly associated with MLH1 methylation [15].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, CIMP positivity, albeit without MLH1 methylation, is reportedly associated with a poor prognosis in DA patients [15]. An earlier study analyzed DNA methylation in ampullary and non‐ampullary duodenal adenomas, but that study did not analyze these tumor types separately [16]. Thus, epigenetic alterations in early non‐ampullary duodenal lesions remain to be elucidated.…”

Section: Introductionmentioning

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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confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Prior studies on molecular events in NADCs have focused on genetic events 7,10,13–18,28 , and there have been few studies evaluating epigenetic alterations 6,9,12,16 . There have also been no studies of the associations among clinicopathological, immunohistochemical (including PD-L1 expression) and molecular characteristics; our study is the first to explore these associations in NADC, although a single study evaluated the associations in SBA 27 .…”

Section: Discussionmentioning

confidence: 99%

“…However, CIMP was associated with MSI in those studies, contrary to our present finding. According to the studies analyzing duodenal adenomas and DACs 9,12 , CIMP is an early event in tumorigenesis and may be lost in later stages of tumor progression; alternatively, advanced-stage DACs may arise from different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Molecular alterations and PD-L1 expression in non-ampullary duodenal adenocarcinoma: Associations among clinicopathological, immunophenotypic and molecular features

Watari

Mitani

Ito

et al. 2019

Sci Rep

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Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we retrospectively analyzed the cases of 32 NADC patients, focusing on microsatellite instability (MSI), genetic mutations, CpG island methylator phenotype (CIMP), and immunostaining including mucin phenotype and PD-L1 expression. The incidence of MSI, KRAS / BRAF / GNAS mutations and CIMP was 51.6%, 34.4%/3.1%/6.5% and 28.1%, respectively. PD-L1 expression was seen in 34.4% of patients. No significant associations between clinicopathological features and KRAS / BRAF / GNAS genetic mutations or CIMP were found. Histologically non-well-differentiated-type NADCs and those in the 1st portion of the duodenum were significantly associated with later stages (stages III–IV) ( P = 0.006 and P = 0.003, respectively). Gastric-phenotype NADCs were frequently observed in the 1st portion and in late-stage patients; their cancer cells more frequently expressed PD-L1. Histologically, the non-well-differentiated type was an independent predictor of PD-L1 expression in cancer cells (OR 25.05, P = 0.04) and immune cells (OR 44.14, P = 0.02). Only late-stage disease (HR 12.23, P = 0.01) was a prognostic factor for worse overall survival in a Cox proportional hazards regression model. Our observation of high proportions of MSI and PD-L1 expression may prompt the consideration of immune checkpoint inhibitors as a new treatment option for NADCs.

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Duodenal and Papillary Adenomas

Klein¹,

Bourke²

2019

Clinical Gastrointestinal Endoscopy

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CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

Cited by 7 publications

References 40 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

Molecular alterations and PD-L1 expression in non-ampullary duodenal adenocarcinoma: Associations among clinicopathological, immunophenotypic and molecular features

Duodenal and Papillary Adenomas

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