The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Molecular alterations underlying inflammatory bowel disease-associated neoplasia and preneoplasia (IBDN) have been studied extensively over the past 10 years. Perhaps the most interesting facet of these studies has been the emergence of IBDN as a distinct form of colorectal neoplasia, with both similarities to and differences from sporadic colorectal neoplasia and preneoplasia (SCN). This finding of differences between IBDN and SCN should not surprise IBD clinicians, who are quite familiar with the known biologic differences between these two forms of neoplasia. For example, it is widely held that the interval between dysplasia and frank carcinoma is only a few years in IBDN, contrasted with 10-15 years or longer for SCN. Furthermore, frank carcinoma in IBDN often evolves from flat dysplastic lesions, whereas SCN is commonly believed to evolve from polypoid dysplasias (adenomas). Finally, IBDN develops in a setting of intense mucosal inflammation, often after 20 or more years of nondysplastic IBD; SCN typically develops on a substratum of non-inflamed colonic mucosa. Investigations of IBDN, however, have closely paralleled the investigative paradigm estabhshed in SCN by Bert Vogelstein and his coUeagues [1]. Early in the history of these analyses, proto-oncogenes of the ras family were studied [2-5]. Later, loss of heterozygosity (LOH) was evaluated, and evaluations of tumor-suppressor genes (TSG) evolved directly from these LOH studies [1, 6-10]. Subsequently, the unique form of mutation known as microsatellite instability (MSI) was evaluated in IBDN, and the ramifications of this form of mutation were investigated [11-16]. This form of mutation comprises length mutations in oligonucleotide repeat sequences, typically in non-coding regions of genomic DNA. The ability of MSI to target specific coding regions was also evaluated in IBDN [17-19]. MSI is caused by inactivation or defective function of DNA mismatch repair (MMR) genes [20-24]. Finally, gene inactivation by promoter hypermethylation was studied in IBDN [25]. Hypermethylation appears to be of pivotal importance in IBDN, since it inactivates TSG such as the cyclindependent kinase inhibitor pi6 [26] along with MMR genes [25]. In the future comprehensive new molecularly based taxonomies may augment traditional approaches to classifying IBDN. In particular, gene expression 'signatures', or profiles of the expression levels of thousands of genes generated by cDNA microarrays, promise to shed light not only on new taxonomies, but also on novel molecular genetic pathways involved in IBDN [27-35]. Genes involved in these pathways offer the potential to serve as biomarkers of cancer risk and disease progression; moreover, they present promising targets of future molecular and pharmacologic cancer prevention and treatment strategies.

Original languageEnglish (US)
Title of host publicationInflammatory Bowel Disease: From Bench to Bedside
PublisherSpringer US
Pages711-718
Number of pages8
ISBN (Print)0387258078, 9788847004337
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Molecular Pathology
Inflammatory Bowel Diseases
Neoplasms
Microsatellite Instability
Mutation
DNA Mismatch Repair
Loss of Heterozygosity
Tumor Suppressor Genes
Transcriptome
Genes
Carcinoma

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia. / Meltzer, Stephen.

Inflammatory Bowel Disease: From Bench to Bedside. Springer US, 2006. p. 711-718.

Research output: Chapter in Book/Report/Conference proceedingChapter

Meltzer, Stephen. / The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia. Inflammatory Bowel Disease: From Bench to Bedside. Springer US, 2006. pp. 711-718
@inbook{d125e313b9db4a22ab5dd97164295b10,
title = "The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia",
abstract = "Molecular alterations underlying inflammatory bowel disease-associated neoplasia and preneoplasia (IBDN) have been studied extensively over the past 10 years. Perhaps the most interesting facet of these studies has been the emergence of IBDN as a distinct form of colorectal neoplasia, with both similarities to and differences from sporadic colorectal neoplasia and preneoplasia (SCN). This finding of differences between IBDN and SCN should not surprise IBD clinicians, who are quite familiar with the known biologic differences between these two forms of neoplasia. For example, it is widely held that the interval between dysplasia and frank carcinoma is only a few years in IBDN, contrasted with 10-15 years or longer for SCN. Furthermore, frank carcinoma in IBDN often evolves from flat dysplastic lesions, whereas SCN is commonly believed to evolve from polypoid dysplasias (adenomas). Finally, IBDN develops in a setting of intense mucosal inflammation, often after 20 or more years of nondysplastic IBD; SCN typically develops on a substratum of non-inflamed colonic mucosa. Investigations of IBDN, however, have closely paralleled the investigative paradigm estabhshed in SCN by Bert Vogelstein and his coUeagues [1]. Early in the history of these analyses, proto-oncogenes of the ras family were studied [2-5]. Later, loss of heterozygosity (LOH) was evaluated, and evaluations of tumor-suppressor genes (TSG) evolved directly from these LOH studies [1, 6-10]. Subsequently, the unique form of mutation known as microsatellite instability (MSI) was evaluated in IBDN, and the ramifications of this form of mutation were investigated [11-16]. This form of mutation comprises length mutations in oligonucleotide repeat sequences, typically in non-coding regions of genomic DNA. The ability of MSI to target specific coding regions was also evaluated in IBDN [17-19]. MSI is caused by inactivation or defective function of DNA mismatch repair (MMR) genes [20-24]. Finally, gene inactivation by promoter hypermethylation was studied in IBDN [25]. Hypermethylation appears to be of pivotal importance in IBDN, since it inactivates TSG such as the cyclindependent kinase inhibitor pi6 [26] along with MMR genes [25]. In the future comprehensive new molecularly based taxonomies may augment traditional approaches to classifying IBDN. In particular, gene expression 'signatures', or profiles of the expression levels of thousands of genes generated by cDNA microarrays, promise to shed light not only on new taxonomies, but also on novel molecular genetic pathways involved in IBDN [27-35]. Genes involved in these pathways offer the potential to serve as biomarkers of cancer risk and disease progression; moreover, they present promising targets of future molecular and pharmacologic cancer prevention and treatment strategies.",
author = "Stephen Meltzer",
year = "2006",
doi = "10.1007/0-387-25808-6_36",
language = "English (US)",
isbn = "0387258078",
pages = "711--718",
booktitle = "Inflammatory Bowel Disease: From Bench to Bedside",
publisher = "Springer US",

}

TY - CHAP

T1 - The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia

AU - Meltzer, Stephen

PY - 2006

Y1 - 2006

N2 - Molecular alterations underlying inflammatory bowel disease-associated neoplasia and preneoplasia (IBDN) have been studied extensively over the past 10 years. Perhaps the most interesting facet of these studies has been the emergence of IBDN as a distinct form of colorectal neoplasia, with both similarities to and differences from sporadic colorectal neoplasia and preneoplasia (SCN). This finding of differences between IBDN and SCN should not surprise IBD clinicians, who are quite familiar with the known biologic differences between these two forms of neoplasia. For example, it is widely held that the interval between dysplasia and frank carcinoma is only a few years in IBDN, contrasted with 10-15 years or longer for SCN. Furthermore, frank carcinoma in IBDN often evolves from flat dysplastic lesions, whereas SCN is commonly believed to evolve from polypoid dysplasias (adenomas). Finally, IBDN develops in a setting of intense mucosal inflammation, often after 20 or more years of nondysplastic IBD; SCN typically develops on a substratum of non-inflamed colonic mucosa. Investigations of IBDN, however, have closely paralleled the investigative paradigm estabhshed in SCN by Bert Vogelstein and his coUeagues [1]. Early in the history of these analyses, proto-oncogenes of the ras family were studied [2-5]. Later, loss of heterozygosity (LOH) was evaluated, and evaluations of tumor-suppressor genes (TSG) evolved directly from these LOH studies [1, 6-10]. Subsequently, the unique form of mutation known as microsatellite instability (MSI) was evaluated in IBDN, and the ramifications of this form of mutation were investigated [11-16]. This form of mutation comprises length mutations in oligonucleotide repeat sequences, typically in non-coding regions of genomic DNA. The ability of MSI to target specific coding regions was also evaluated in IBDN [17-19]. MSI is caused by inactivation or defective function of DNA mismatch repair (MMR) genes [20-24]. Finally, gene inactivation by promoter hypermethylation was studied in IBDN [25]. Hypermethylation appears to be of pivotal importance in IBDN, since it inactivates TSG such as the cyclindependent kinase inhibitor pi6 [26] along with MMR genes [25]. In the future comprehensive new molecularly based taxonomies may augment traditional approaches to classifying IBDN. In particular, gene expression 'signatures', or profiles of the expression levels of thousands of genes generated by cDNA microarrays, promise to shed light not only on new taxonomies, but also on novel molecular genetic pathways involved in IBDN [27-35]. Genes involved in these pathways offer the potential to serve as biomarkers of cancer risk and disease progression; moreover, they present promising targets of future molecular and pharmacologic cancer prevention and treatment strategies.

AB - Molecular alterations underlying inflammatory bowel disease-associated neoplasia and preneoplasia (IBDN) have been studied extensively over the past 10 years. Perhaps the most interesting facet of these studies has been the emergence of IBDN as a distinct form of colorectal neoplasia, with both similarities to and differences from sporadic colorectal neoplasia and preneoplasia (SCN). This finding of differences between IBDN and SCN should not surprise IBD clinicians, who are quite familiar with the known biologic differences between these two forms of neoplasia. For example, it is widely held that the interval between dysplasia and frank carcinoma is only a few years in IBDN, contrasted with 10-15 years or longer for SCN. Furthermore, frank carcinoma in IBDN often evolves from flat dysplastic lesions, whereas SCN is commonly believed to evolve from polypoid dysplasias (adenomas). Finally, IBDN develops in a setting of intense mucosal inflammation, often after 20 or more years of nondysplastic IBD; SCN typically develops on a substratum of non-inflamed colonic mucosa. Investigations of IBDN, however, have closely paralleled the investigative paradigm estabhshed in SCN by Bert Vogelstein and his coUeagues [1]. Early in the history of these analyses, proto-oncogenes of the ras family were studied [2-5]. Later, loss of heterozygosity (LOH) was evaluated, and evaluations of tumor-suppressor genes (TSG) evolved directly from these LOH studies [1, 6-10]. Subsequently, the unique form of mutation known as microsatellite instability (MSI) was evaluated in IBDN, and the ramifications of this form of mutation were investigated [11-16]. This form of mutation comprises length mutations in oligonucleotide repeat sequences, typically in non-coding regions of genomic DNA. The ability of MSI to target specific coding regions was also evaluated in IBDN [17-19]. MSI is caused by inactivation or defective function of DNA mismatch repair (MMR) genes [20-24]. Finally, gene inactivation by promoter hypermethylation was studied in IBDN [25]. Hypermethylation appears to be of pivotal importance in IBDN, since it inactivates TSG such as the cyclindependent kinase inhibitor pi6 [26] along with MMR genes [25]. In the future comprehensive new molecularly based taxonomies may augment traditional approaches to classifying IBDN. In particular, gene expression 'signatures', or profiles of the expression levels of thousands of genes generated by cDNA microarrays, promise to shed light not only on new taxonomies, but also on novel molecular genetic pathways involved in IBDN [27-35]. Genes involved in these pathways offer the potential to serve as biomarkers of cancer risk and disease progression; moreover, they present promising targets of future molecular and pharmacologic cancer prevention and treatment strategies.

UR - http://www.scopus.com/inward/record.url?scp=84891398298&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891398298&partnerID=8YFLogxK

U2 - 10.1007/0-387-25808-6_36

DO - 10.1007/0-387-25808-6_36

M3 - Chapter

AN - SCOPUS:84891398298

SN - 0387258078

SN - 9788847004337

SP - 711

EP - 718

BT - Inflammatory Bowel Disease: From Bench to Bedside

PB - Springer US

ER -