PMC:1852721 / 63271-67779 JSONTXT

{"project":"2_test","denotations":[{"id":"17357067-12042769-2054087","span":{"begin":2104,"end":2106},"obj":"12042769"},{"id":"17357067-12082624-2054088","span":{"begin":3221,"end":3223},"obj":"12082624"},{"id":"17357067-6185846-2054089","span":{"begin":3740,"end":3742},"obj":"6185846"},{"id":"17357067-12637750-2054090","span":{"begin":4226,"end":4228},"obj":"12637750"}],"text":"Epigenetic Variation in MIM/OMIM\nIn both the phenotype and the gene entries in MIM/OMIM, much information is recorded about epigenetic variation. This is variation in gene expression that is not encoded in the DNA sequence itself. The many areas of epigenetics touched on in MIM/OMIM include aspects of X-chromosome inactivation, autosomal imprinting, the role of methylation and histone modification, and the implications for the pattern of inheritance and phenotype of Mendelian disorders and for the pathogenesis of certain developmental abnormalities such as Beckwith-Wiedemann syndrome (MIM #130650) and many cancers.\nDiscussions of X-chromosome inactivation include the role of specific genes in the creation or maintenance of the inactive state—for example, XIST (MIM *314670), TSIX (MIM *300181), and XCE (MIM *300074). Familial skewed X inactivation (MIM #300087) is sometimes due to mutations in the XIST gene; skewed X inactivation occurs also in women heterozygous for some X-linked disorders, including X-linked severe combined immunodeficiency (MIM #300400), Wiskott-Aldrich syndrome (MIM #301000), and dyskeratosis congenita (MIM #305000), in which cells with the mutation-carrying X chromosomes are at a selective disadvantage. In such instances, the skewing can be used as a method for diagnosing the heterozygous carrier state. In some instances, skewed inactivation may be a main piece of evidence establishing X-linked inheritance; for example, Aicardi syndrome (MIM %304050) is probably X-linked dominant with male lethality, to judge from the finding of skewed X inactivation in females.\nAutosomal imprinting is involved in the phenotypic consequences of uniparental disomy. A prime example is provided by Prader-Willi syndrome (MIM #176270) in individuals with maternal uniparental disomy for chromosome 15; since both chromosomes 15 come from the mother, the individual lacks the paternally expressed gene IPW (MIM *601491) located in proximal 15q.\nThe epigenetic silencing of tumor-suppressor genes may be a more frequent basis for cancer than are point mutations in those genes.43 Aberrant promoter methylation is associated with loss-of-gene function that can provide a selective advantage to neoplastic cells, just as do loss-of- function point mutations. Germline mutations in the VHL (MIM *608537), BRCA1 (MIM +113705), and STK11 (MIM *602216) genes cause familial forms of renal, breast, and colon cancers, respectively; the same genes are often epigenetically silenced in sporadic forms of these tumors. For example, the BRCA1 gene is not important only for familial breast cancer; 10%–15% of women with nonfamilial breast cancer have tumors in which the BRCA1 gene is hypermethylated.\nThus, in addition to the \u003e2,000 genes for which one or more specific disease-related mutations have been found, other genes cataloged in OMIM are important to the pathogenesis of cancers through epigenetic mechanisms. These are tumor-suppressor genes silenced through hypermethylation. Examples include the RASSF1 gene (MIM *605082) on 3p21, which is often deleted or its promoter hypermethylated in lung cancer. This gene shows anomalous promoter hypermethylation in a large number of other tumor types72 as well. As indicated by their names, other tumor-suppressor genes related to cancers through epigenetic silencing are “hypermethylated in cancer-1” (HIC1 [MIM *603825]) on 17p and “hypermethylated in cancer-2” (HIC2 [MIM *607712]) on 22q.\nThe converse situation, activation of oncogenes through hypomethylation, also leads to the development of cancers. Indeed, hypomethylation was the first indication of the role of anomalous promoter methylation in carcinogenesis, as reported by Feinberg and Vogelstein in 1983.73\nLoss of imprinting (LOI), an epigenetic alteration, has also been found in cancers. LOI of the gene encoding insulinlike growth factor II (IGF2 [MIM +147470]) has been described for Wilms tumor (MIM #194070), in Beckwith-Wiedemann syndrome (MIM #130650), and in hepatoblastoma. LOI of IGF2 is found in normal colonic mucosa of ∼30% of patients with colorectal cancer (MIM #114500) but in only ∼10% of normal individuals. In a study of 172 patients in a colonoscopy clinic, Cui et al.74 found that the adjusted odds ratio for LOI of IGF2 in lymphocytes was 5.15 for patients with a positive family history, 3.46 for patients with adenomas, and 21.7 for patients with colorectal cancer. Other work supported the idea that LOI of IGF2 may be a familial characteristic."}