hypermutation
noun: a state in which genetic mutation is abnormally frequent
open access
The bile duct system follows the passage of the bile from its production by the liver cells through the intra- and extra-hepatic bile ducts to the duodenum. Along this passageway, the gallbladder serves as a storage organ, storing up to 50% of the bile and releasing it when food is ingested.
Cancers that arise from the various segments of the biliary system exhibit varied clinico-pathological characteristics. Thus, they are traditionally separated into categories based on their specific location in the system: gallbladder carcinoma, intra-hepatic cholangiocarcinoma, hilar or perihilar cholangiocarcinoma, carcinoma of the distal common bile duct, and ampullary carcinoma (1).
Tumorigenesis of the biliary epithelium in general follows the dysplasia to carcinoma sequence.......
Abstract:
The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various epidemiological risk factors, varied genetic makeup, and tissue microenvironment are contributory factors. As biliary tumors have been shown to be a part of the Lynch syndrome tumor spectrum, it is plausible to speculate that DNA mismatch repair (MMR) deficiency plays a role in biliary tumors. Literature data suggest that DNA MMR deficiency indeed occurs in these tumors, albeit infrequently with the reported frequencies (weighted for sample size) of high level microsatellite instability (MSI) being 5% each for gallbladder carcinoma and carcinoma of extra-hepatic bile ducts, and 10% each for intrahepatic cholangiocarcinoma and ampullary carcinoma. Importantly, the presence of MMR deficiency in these tumors has been shown to have different implications with regard to its association with Lynch syndrome, tumor histological features, and other clinical characteristics, when compared with non-biliary tumors or among the biliary tumors from the different segments of the biliary system. Ongoing and future efforts that utilize large scale sequencing techniques and aim at detecting actionable molecular targets should emphasize a multidisciplinary approach that integrates genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor’s clinical and biological behavior.
The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various epidemiological risk factors, varied genetic makeup, and tissue microenvironment are contributory factors. As biliary tumors have been shown to be a part of the Lynch syndrome tumor spectrum, it is plausible to speculate that DNA mismatch repair (MMR) deficiency plays a role in biliary tumors. Literature data suggest that DNA MMR deficiency indeed occurs in these tumors, albeit infrequently with the reported frequencies (weighted for sample size) of high level microsatellite instability (MSI) being 5% each for gallbladder carcinoma and carcinoma of extra-hepatic bile ducts, and 10% each for intrahepatic cholangiocarcinoma and ampullary carcinoma. Importantly, the presence of MMR deficiency in these tumors has been shown to have different implications with regard to its association with Lynch syndrome, tumor histological features, and other clinical characteristics, when compared with non-biliary tumors or among the biliary tumors from the different segments of the biliary system. Ongoing and future efforts that utilize large scale sequencing techniques and aim at detecting actionable molecular targets should emphasize a multidisciplinary approach that integrates genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor’s clinical and biological behavior.
Keywords: Microsatellite instability (MSI); biliary neoplasm; cholangiocarcinoma; gallbladder; bile duct; ampulla
Conclusions and future perspectives
Biliary carcinomas represent a heterogeneous group of tumors resulting from a complex interplay among different causative factors and different microenvironment throughout the biliary system. Consequently, significant heterogeneity exists in tumor pathology and the underlying molecular alterations. It seems certain that DNA MMR deficiency plays a role in some biliary tumors. This role, however, may differ from that seen in other conventional Lynch syndrome associated cancer types, and may vary even within the family of biliary tumors.In the current era of next generation sequencing, it can be anticipated that large scale genomic analysis will allow a more integrated view of the molecular alterations of the various biliary tumors and allow the detection of clinically actionable gene targets. Indeed, a recent study (8) utilizing whole exome sequencing on a series of biliary carcinomas detected an overall 5.9% (14/239) “hypermutated” tumors, and found that some such hypermutated tumors harbored inactivating (nonsense, frameshift or spice-site) mutations in mismatch-repair complex components. More importantly, the analysis detected that cases with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules, suggesting immune-modulating therapies might be potentially beneficial for these patients (8,54).
Given the significant tumor heterogeneity, it is imperative that future efforts on achieving effective detection of clinically actionable molecular targets be site and type specific, and utilizes a multidisciplinary approach integrating genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor’s clinical and biological behavior
Literature review
Pertinent and comparable studies on MMR deficiency in biliary carcinomas are summarized in Table 2.
Table 2 Literature data on DNA MMR deficiency in biliary carcinomas.
Full table
Full table
