Genetics and epigenetics in gastroenterology

Genetics in the context of disease causation refers to gene expression altered by DNA mutations. Epigenetics refers to gene expression altered without DNA mutations, but instead by other cellular mechanisms that will be described here. Together, genetic and epigenetic gene expression determine both physiologic and pathologic cellular processes and functions.

Many areas of gastroenterology are now known to involve these mechanisms as part of disease pathophysiology. The area most investigated in gastroenterology is perhaps colon cancer, which will be used as an example in describing clinically pertinent mechanisms and findings in both genetics and epigenetics.

Inherited DNA mutations of certain genes result in colon cancer susceptibility syndromes. Somatic mutations of many of the same genes are part of colon cancer pathogenesis in common or sporadic cases. Pertinent syndromes include familial adenomatous polyposis (APC gene), Lynch syndrome (mismatch repair genes [MMR]), MUTY-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), juvenile polyposis (SMAD4 and BMPR1A genes), Cowden syndrome (PTEN gene), and variant polyposis (POLE, POLD1, and Gremm1 genes). For each of these syndromes, genetic testing is now an accepted part of clinical management for diagnosis and guidance as to who should receive more aggressive screening and surveillance for colon cancer prevention.

Acquired or somatic mutations of the same and other genes are involved in the process of benign to malignant transformation in the colon. Involved genes are often divided into three pathways, although there is much overlap between these pathways.

The first pathway is the chromosomal instability pathway that begins with acquired APC gene mutations of a colonocyte. These mutations are followed by the accumulation of additional mutations as normal cells progress to forming adenomatous polyps and then cancer. Such genes include KRAS, SMAD, TP53, PTEN, PI3KCA, and perhaps others. The second pathway involves acquired mutations of the mismatch repair genes early in the benign to malignant process, with mutations occurring especially in the MLH1 gene. It is called the microsatellite instability pathway. Different genes are then involved through mutation in this pathway to cancer. These include TGF beta, BAX, IGF2R, and others. The third pathway is called CIMP for “CpG island methylation phenotype.” It is actually an epigenetic pathway and involves the accumulation of mutations in yet other genes including MLH1, WRN, p16, RARB2, BRAF, and possibly many others, and gives rise to both adenomatous polyps and sessile serrated polyps.

Clinical relevance of somatic mutations of the genes in these three pathways is already informing clinical practice. Cancers with MMR gene mutations, for example, exhibit a better prognosis than other colon cancers but a decreased responsiveness to fluorouracil drugs. Tumors with KRAS or BRAF mutations have little or no response to EGFR-inhibitor drugs. Many of the genes in which acquired mutations occur are now interrogated as part of stool DNA screening tests.

Epigenetic processes change gene expression without DNA mutation and include three primary categories: DNA methylation, histone and chromatin changes, and microRNA changes.

Half of human genes have promotor regions rich in CpG islands. When methylation occurs in these CpG islands, gene expression is usually inhibited. This is the main mechanism of the CIMP pathway and in turn affects numerous cell functions important to cancer pathogenesis. Histones are proteins around which DNA coils. The proteins with coiled DNA are called chromatin units. Histones have protein tails that repress gene transcription when acetylation and specific methylations occur. Some histone proteins have already been observed to be overexpressed in colon cancer. MicroRNAs are short noncoding RNAs that induce gene repression in up to 30% of genes. Altered MicroRNA expression has been observed in many colon cancer–associated genes, and specific microRNA patterns have characterized certain colon cancers.

Epigenetic cancer markers are only beginning to be understood but are being examined for use in early detection and prognosis, tumor subclassifications, following the effectiveness of chemotherapy, and providing targets of intervention.

In summary, colon cancer genetics has provided genetic testing for inherited syndromes and guides to therapy with acquired mutations, while epigenetic mechanisms have the potential of being important to many areas of cancer diagnosis and treatment.

Dr. Burt is professor of medicine and holder of the Barnes Presidential Endowed Chair in Medicine at the Huntsman Cancer Institute and the University of Utah, Salt Lake City. He has consulted for Myriad Genetics. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Genetics in the context of disease causation refers to gene expression altered by DNA mutations. Epigenetics refers to gene expression altered without DNA mutations, but instead by other cellular mechanisms that will be described here. Together, genetic and epigenetic gene expression determine both physiologic and pathologic cellular processes and functions.

Many areas of gastroenterology are now known to involve these mechanisms as part of disease pathophysiology. The area most investigated in gastroenterology is perhaps colon cancer, which will be used as an example in describing clinically pertinent mechanisms and findings in both genetics and epigenetics.

Inherited DNA mutations of certain genes result in colon cancer susceptibility syndromes. Somatic mutations of many of the same genes are part of colon cancer pathogenesis in common or sporadic cases. Pertinent syndromes include familial adenomatous polyposis (APC gene), Lynch syndrome (mismatch repair genes [MMR]), MUTY-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), juvenile polyposis (SMAD4 and BMPR1A genes), Cowden syndrome (PTEN gene), and variant polyposis (POLE, POLD1, and Gremm1 genes). For each of these syndromes, genetic testing is now an accepted part of clinical management for diagnosis and guidance as to who should receive more aggressive screening and surveillance for colon cancer prevention.

Acquired or somatic mutations of the same and other genes are involved in the process of benign to malignant transformation in the colon. Involved genes are often divided into three pathways, although there is much overlap between these pathways.

The first pathway is the chromosomal instability pathway that begins with acquired APC gene mutations of a colonocyte. These mutations are followed by the accumulation of additional mutations as normal cells progress to forming adenomatous polyps and then cancer. Such genes include KRAS, SMAD, TP53, PTEN, PI3KCA, and perhaps others. The second pathway involves acquired mutations of the mismatch repair genes early in the benign to malignant process, with mutations occurring especially in the MLH1 gene. It is called the microsatellite instability pathway. Different genes are then involved through mutation in this pathway to cancer. These include TGF beta, BAX, IGF2R, and others. The third pathway is called CIMP for “CpG island methylation phenotype.” It is actually an epigenetic pathway and involves the accumulation of mutations in yet other genes including MLH1, WRN, p16, RARB2, BRAF, and possibly many others, and gives rise to both adenomatous polyps and sessile serrated polyps.

Clinical relevance of somatic mutations of the genes in these three pathways is already informing clinical practice. Cancers with MMR gene mutations, for example, exhibit a better prognosis than other colon cancers but a decreased responsiveness to fluorouracil drugs. Tumors with KRAS or BRAF mutations have little or no response to EGFR-inhibitor drugs. Many of the genes in which acquired mutations occur are now interrogated as part of stool DNA screening tests.

Epigenetic processes change gene expression without DNA mutation and include three primary categories: DNA methylation, histone and chromatin changes, and microRNA changes.

Half of human genes have promotor regions rich in CpG islands. When methylation occurs in these CpG islands, gene expression is usually inhibited. This is the main mechanism of the CIMP pathway and in turn affects numerous cell functions important to cancer pathogenesis. Histones are proteins around which DNA coils. The proteins with coiled DNA are called chromatin units. Histones have protein tails that repress gene transcription when acetylation and specific methylations occur. Some histone proteins have already been observed to be overexpressed in colon cancer. MicroRNAs are short noncoding RNAs that induce gene repression in up to 30% of genes. Altered MicroRNA expression has been observed in many colon cancer–associated genes, and specific microRNA patterns have characterized certain colon cancers.

Epigenetic cancer markers are only beginning to be understood but are being examined for use in early detection and prognosis, tumor subclassifications, following the effectiveness of chemotherapy, and providing targets of intervention.

In summary, colon cancer genetics has provided genetic testing for inherited syndromes and guides to therapy with acquired mutations, while epigenetic mechanisms have the potential of being important to many areas of cancer diagnosis and treatment.

Dr. Burt is professor of medicine and holder of the Barnes Presidential Endowed Chair in Medicine at the Huntsman Cancer Institute and the University of Utah, Salt Lake City. He has consulted for Myriad Genetics. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Genetics in the context of disease causation refers to gene expression altered by DNA mutations. Epigenetics refers to gene expression altered without DNA mutations, but instead by other cellular mechanisms that will be described here. Together, genetic and epigenetic gene expression determine both physiologic and pathologic cellular processes and functions.

Many areas of gastroenterology are now known to involve these mechanisms as part of disease pathophysiology. The area most investigated in gastroenterology is perhaps colon cancer, which will be used as an example in describing clinically pertinent mechanisms and findings in both genetics and epigenetics.

Inherited DNA mutations of certain genes result in colon cancer susceptibility syndromes. Somatic mutations of many of the same genes are part of colon cancer pathogenesis in common or sporadic cases. Pertinent syndromes include familial adenomatous polyposis (APC gene), Lynch syndrome (mismatch repair genes [MMR]), MUTY-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), juvenile polyposis (SMAD4 and BMPR1A genes), Cowden syndrome (PTEN gene), and variant polyposis (POLE, POLD1, and Gremm1 genes). For each of these syndromes, genetic testing is now an accepted part of clinical management for diagnosis and guidance as to who should receive more aggressive screening and surveillance for colon cancer prevention.

Acquired or somatic mutations of the same and other genes are involved in the process of benign to malignant transformation in the colon. Involved genes are often divided into three pathways, although there is much overlap between these pathways.

The first pathway is the chromosomal instability pathway that begins with acquired APC gene mutations of a colonocyte. These mutations are followed by the accumulation of additional mutations as normal cells progress to forming adenomatous polyps and then cancer. Such genes include KRAS, SMAD, TP53, PTEN, PI3KCA, and perhaps others. The second pathway involves acquired mutations of the mismatch repair genes early in the benign to malignant process, with mutations occurring especially in the MLH1 gene. It is called the microsatellite instability pathway. Different genes are then involved through mutation in this pathway to cancer. These include TGF beta, BAX, IGF2R, and others. The third pathway is called CIMP for “CpG island methylation phenotype.” It is actually an epigenetic pathway and involves the accumulation of mutations in yet other genes including MLH1, WRN, p16, RARB2, BRAF, and possibly many others, and gives rise to both adenomatous polyps and sessile serrated polyps.

Clinical relevance of somatic mutations of the genes in these three pathways is already informing clinical practice. Cancers with MMR gene mutations, for example, exhibit a better prognosis than other colon cancers but a decreased responsiveness to fluorouracil drugs. Tumors with KRAS or BRAF mutations have little or no response to EGFR-inhibitor drugs. Many of the genes in which acquired mutations occur are now interrogated as part of stool DNA screening tests.

Epigenetic processes change gene expression without DNA mutation and include three primary categories: DNA methylation, histone and chromatin changes, and microRNA changes.

Half of human genes have promotor regions rich in CpG islands. When methylation occurs in these CpG islands, gene expression is usually inhibited. This is the main mechanism of the CIMP pathway and in turn affects numerous cell functions important to cancer pathogenesis. Histones are proteins around which DNA coils. The proteins with coiled DNA are called chromatin units. Histones have protein tails that repress gene transcription when acetylation and specific methylations occur. Some histone proteins have already been observed to be overexpressed in colon cancer. MicroRNAs are short noncoding RNAs that induce gene repression in up to 30% of genes. Altered MicroRNA expression has been observed in many colon cancer–associated genes, and specific microRNA patterns have characterized certain colon cancers.

Epigenetic cancer markers are only beginning to be understood but are being examined for use in early detection and prognosis, tumor subclassifications, following the effectiveness of chemotherapy, and providing targets of intervention.

In summary, colon cancer genetics has provided genetic testing for inherited syndromes and guides to therapy with acquired mutations, while epigenetic mechanisms have the potential of being important to many areas of cancer diagnosis and treatment.

Dr. Burt is professor of medicine and holder of the Barnes Presidential Endowed Chair in Medicine at the Huntsman Cancer Institute and the University of Utah, Salt Lake City. He has consulted for Myriad Genetics. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.