Very low incidence of microsatellite instability in intraductal papillary‐mucinous neoplasm of the pancreas

Nakata, Bunzo; Yashiro, Masakazu; Nishioka, Nobuaki; Aya, Makoto; Yamada, Shinobu; Takenaka, Chiemi; Ohira, Masaichi; Ishikawa, Tetsuro; Nishino, Hiroji; Wakasa, Kenichi; Seki, Shuichi; Hirakawa, Kosei

doi:10.1002/ijc.10771

Cited by 24 publications

(17 citation statements)

References 22 publications

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“…39,40,42 Further, IPMNs are also known to be mostly microsatellite stable. 43,44 In line with our study, Amato et al found TP53 mutation from 5/48 IPMN tumors and all of the TP53 mutated ones were HG tumors. 40 Our results of sequencing the most common mutational hotspot areas of 48 cancer-related genes from 19 PMP tumors indicate that the most frequent mutated genes in PMP tumors are KRAS and GNAS.…”

Section: Discussionsupporting

confidence: 91%

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Nummela

Saarinen

Thiel

et al. 2014

Intl Journal of Cancer

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Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n 5 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared with low-grade ones (31.3 vs. 7.1%, respectively; p 5 0.012) and aberrant expression was an independent factor for reduced overall survival (p 5 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n 5 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival.Pseudomyxoma peritonei (PMP) is a relatively rare subtype of mucinous adenocarcinoma with estimated incidence of one to two persons per million per year. 1 PMP arises most often from mucinous neoplasms of the appendix, which leak tumor cells into the peritoneal cavity, colonize peritoneal cavity and produce abundant mucinous ascites. The classical low-grade (LG) form of PMP has been considered to be a rather benign disease, as it progresses slowly and does not by the definition show invasive characteristics. However, progressive obstruction makes even the LG form of PMP a fatal disease. In contrast, high-grade (HG) PMP possess invasive and metastasizing capacity with the 5-year survival being as low as 23%, while for the LG disease it is 63%. 2 At the moment, the optimal treatment for PMP is aggressive cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). 3 In addition to PMP-related mortality, these complex treatments are, however, associated with considerable morbidity and mortality. 4 Furthermore, not all patients are amenable to these treatment options. 5 Thus, targeted therapies, even ones that would reduce mucin production, would be important additions to the treatment arsenal for PMP patients. To this end, biomarkers and prognostic factors would be helpful to estimate the aggressiveness of the disease and direct personalized treatment options...

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Section: Discussionsupporting

confidence: 91%

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Nummela

Saarinen

Thiel

et al. 2014

Intl Journal of Cancer

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“…In contrast to ductal adenocarcinoma in which loss of the DPC4 ( SMAD4 ) gene occurs in 50% of the cases, DPC4 loss is very uncommon in IPMNs as well as in invasive colloid carcinoma 18 48 49 60 61. Cox2 expression is not uncommon in IPMNs and might have a role in chemoprevention with anti-Cox2 agents 7.…”

Section: Anatomical Classificationmentioning

confidence: 99%

Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach

Katabi

Klimstra

2008

J Clin Pathol

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Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing neoplasms with a frequent papillary architecture that arise within the pancreatic ducts and are increasingly being recognised. Because they exhibit a spectrum of dysplasia ranging from low grade to high grade and may also have associated invasive carcinoma, and because they are clinically detectable, they are now intensively studied. There is marked overlap between IPMNs and pancreatic intraepithelial neoplasia (PanIN), such that the distinction between these two lesions is nearly impossible in certain cases. In addition, IPMNs sometimes can be confused with other primary cystic lesions of the pancreas. As a result, the correct diagnosis of IPMN can be challenging. This review addresses the clinical and pathological features of IPMNs, emphasising their diagnostic criteria, differential diagnosis and biological behaviour. Problematic issues in the pathological evaluation of IPMNs are discussed.

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“…This does not exclude entirely the possibility of involvement of other components of the DNA mismatch repair system, such as hMSH6 and hPMS2 genes, or of other mechanisms, such as the presence of a missense mutation resulting in a nonfunctional immunoreactive protein [11]. However, pathways that do not involve hypermethylation or germinal mutations seem to be more frequently encountered in pancreatic carcinomas [10,13] than in colorectal carcinomas. This could be explained by the occurrence of tissue-specific mechanisms of inactivation of mismatch repair (MMR) genes and involve target genes/pathways [4] in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 81%

Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas

Couvelard

Degott

Fléjou³

2004

Virchows Archiv

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Defective DNA mismatch repair results from genetic or epigenetic alterations that most frequently inactivate the genes hMLH1 and hMSH2. This is thought to promote tumourigenesis by accumulation of mutations in oncogenes and tumour suppressor genes. This pathway, first reported in colon cancer, has been recently demonstrated in a subgroup of sporadic pancreatic adenocarcinomas. Intraductal papillary-mucinous neoplasms of the pancreas are a special type of pancreatic tumours, characterised by a spectrum of morphological changes from mild to moderate and to non-invasive, and they may associate with adenocarcinoma. An immunohistochemical study of hmlh1 and hmsh2 protein expression was performed on 26 intraductal papillary-mucinous neoplasms. All tumours showed nuclear expression of hmlh1 and hmsh2 proteins. There were two distinctive patterns of protein expression on the basis of the location of cells expressing these markers: the "normal" pattern, observed mainly in adenoma and rarely in intraductal papillary-mucinous neoplasms with moderate dysplasia and the "dysplastic" pattern, frequently encountered in moderate dysplasia neoplasms, non-invasive and invasive carcinomas. These findings suggest that defective DNA mismatch repair, due to inactivation of hMLH1 and hMSH2, does not play a significant role in the pathogenesis of intraductal papillary-mucinous neoplasms of the pancreas. Two patterns of protein expression were observed and were correlated with the progression of dysplasia in intraductal papillary mucinous neoplasms.

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Very low incidence of microsatellite instability in intraductal papillary‐mucinous neoplasm of the pancreas

Cited by 24 publications

References 22 publications

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach

Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas

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