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Hitchins, M. et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129, 1392-1399

University of Newcastle, Newcastle, New South Wales, Australia
Gastroenterology (Impact Factor: 13.93). 11/2005; 129(5):1392-9. DOI: 10.1053/j.gastro.2005.09.003
Source: PubMed

ABSTRACT Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous germline sequence mutations of DNA mismatch repair genes, most frequently MLH1 or MSH2. A novel molecular mechanism for HNPCC has recently been suggested by the finding of individuals with soma-wide monoallelic hypermethylation of the MLH1 gene promoter. In this study, we determined the frequency and role of germline epimutations of MLH1 in HNPCC.
A cohort of 160 probands from HNPCC families who did not harbor germline sequence mutations in the mismatch repair genes were screened for methylation of the MLH1 and EPM2AIP1 promoters by combined bisulfite and restriction analyses. Allelic expression and family transmission of MLH1 were determined using polymorphisms in intron 4 and the 3' untranslated region.
One of 160 individuals had monoallelic MLH1 hypermethylation in peripheral blood, hair follicles, and buccal mucosa, indicative of a soma-wide alteration. Monoallelic transcription of the paternal MLH1 allele was shown using a heterozygous expressed polymorphism within the 3' untranslated region. The hypermethylated allele was maternally transmitted, however, the mother and siblings who inherited the same maternal homologue were unmethylated at MLH1, suggesting the epimutation arose as a de novo event.
Germline MLH1 epimutations are functionally equivalent to an inactivating mutation and produce a clinical phenotype that resembles HNPCC. Inheritance of epimutations is weak, so family history is not a useful guide for screening. Germline epimutations should be suspected in younger individuals without a family history who present with a microsatellite unstable tumor showing loss of MLH1 expression.

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    • "Specifically, transgenerational epigenetic inheritance in humans may result in illnesses due to epimutations that are then passed on to progeny. One known case of epigenetic inheritance is increased risk for hereditary non-polyposis colorectal cancer (HNPCC), a sporadic colorectal cancer with mismatch repair deficiency due to genetic mutations or hypermethylation, particularly of MLH1 or MSH2 mismatch repair genes (Hitchins et al., 2005; Hesson et al., 2010). Mutations of MSH6, PMS2, and MLH3 have also been associated with a small number of HNPCC cases (Rustgi, 2007). "
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    ABSTRACT: Epigenetic information can be passed on from one generation to another via DNA methylation, histone modifications, and changes in small RNAs, a process called epigenetic memory. During a mammal's lifecycle epigenetic reprogramming, or the resetting of most epigenetic marks, occurs twice. The first instance of reprogramming occurs in primordial germ cells and the second occurs following fertilization. These processes may be both passive and active. In order for epigenetic inheritance to occur the epigenetic modifications must be able to escape reprogramming. There are several examples supporting this non-Mendelian mechanism of inheritance including the prepacking of early developmental genes in histones instead of protamines in sperm, genomic imprinting via methylation marks, the retention of CenH3 in mammalian sperm and the inheritance of piwi-associated interfering RNAs. The ability of mammals to pass on epigenetic information to their progeny provides clear evidence that inheritance is not restricted to DNA sequence and epigenetics plays a key role in producing viable offspring.
    Frontiers in Genetics 06/2011; 2:28. DOI:10.3389/fgene.2011.00028
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    • "Silencing of the MLH1 allele was detectable in all three germ layers, suggesting that an epimutation had occurred in the parental germ line. Some siblings inherited the same allele in an unmethylated state, and no DNA mutations were identified in the MLH1 coding or promoter regions, supporting the idea that this was a case of transgenerational epigenetic inheritance (Hitchins et al. 2005). However, a mechanism for the MLH1 epimutation has yet to be identified, and trans-acting genetic alterations cannot be ruled out (Hesson et al. 2010). "
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    Genome Research 11/2010; 20(12):1623-8. DOI:10.1101/gr.106138.110 · 13.85 Impact Factor
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    • "Patients with a tumour with MSI and somatic hypermethylation of the MLH1 promoter rarely carry a germline mutation in the MMR system, although rare exceptions have been reported. A few families have been described in which Lynch syndrome patients display hypermethylation of the MLH1 promoter in tumour as well as in non-tumour tissue (Gazzoli et al, 2002; Miyakura et al, 2004; Suter et al, 2004; Hitchins et al, 2005; Valle et al, 2007a). "
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    ABSTRACT: The cancer risk is unknown for those families in which a microsatellite instable tumour is neither explained by MLH1 promoter methylation nor by a germline mutation in a mismatch repair (MMR) gene. Such information is essential for genetic counselling. Families suspected of Lynch syndrome (n = 614) were analysed for microsatellite instability, MLH1 promoter methylation and/or germline mutations in MLH1, MSH2, MSH6, and PMS2. Characteristics of the 76 families with a germline mutation (24 MLH1, 2 PMS2, 32 MSH2, and 18 MSH6) were compared with those of 18 families with an unexplained microsatellite instable tumour. The mean age at diagnosis of the index patients in both groups was comparable at 44 years. Immunohistochemistry confirmed the loss of an MMR protein. Together this suggests germline inactivation of a known gene. The Amsterdam II criteria were fulfilled in 50/75 families (66%) that carried a germline mutation in an MMR gene and in only 2/18 families (11%) with an unexplained microsatellite instable tumour (P<0.0001). Current diagnostic strategies can detect almost all highly penetrant MMR gene mutations. Patients with an as yet unexplained microsatellite instable tumour likely carry a different type of mutation that confers a lower risk of cancer for relatives.
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