Original Article
Brief Report
Inheritance of a Cancer-Associated MLH1 Germ-Line Epimutation
N Engl J Med 2007; 356:697-705February 15, 2007
- Abstract
Persons who have hypermethylation of one allele of MLH1 in somatic cells throughout the body (a germ-line epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the families of two such persons, we found evidence that the epimutation was transmitted from a mother to her son but was erased in his spermatozoa. The affected maternal allele was inherited by three other siblings from these two families, but in those offspring the allele had reverted to the normal active state. These findings demonstrate a novel pattern of inheritance of cancer susceptibility and are consistent with transgenerational epigenetic inheritance.
Media in This Article
Figure 1
Germ-Line Epimutation and Allelic Loss of Expression of MLH1 in Patients A and B.Figure 2
Pedigrees of Patients A and B Showing Intergenerational Transmission of the MLH1 Epimutation and Haplotypes.Article Activity
- Article
Hereditary nonpolyposis colorectal cancer results from germ-line sequence mutations in mismatch-repair genes, particularly MLH1 and MSH2. Somatic inactivation of the remaining normal allele by genetic or epigenetic events leads to the development of microsatellite instability in tumors of the colorectum or endometrium at a young age.1 Methylation of cytosines that precede a guanosine in the DNA sequence (the CpG dinucleotide) is a key epigenetic modification, and hypermethylation of gene promoters is associated with transcriptional silencing.2 In sporadic colorectal cancer, methylation of both alleles of the promoter of MLH1 occurs as a somatic event early in tumorigenesis and is seen in approximately 15% of patients.3
Studies have shown that hypermethylation of MLH1 is not limited to neoplastic cells. Rather, in some persons, hypermethylation of a single allele of MLH1 originates in the germ line and is thus widespread in normal somatic cells.4-7 This phenomenon of germ-line epimutation silences the affected allele in the absence of intragenic sequence mutations. Persons with a germ-line epimutation, like those with hereditary nonpolyposis colorectal cancer, have only one functional allele of the MLH1 gene from conception, and cancers typical of the hereditary nonpolyposis colorectal cancer syndrome have developed in all such cases described to date.4-7 Colorectal and other tumors in persons with MLH1 germ-line epimutations do not express the MLH1 protein and have microsatellite instability (the hallmark of failed mismatch-repair function), accompanied in some cases by somatic loss of the wild-type allele.4-7
Although germ-line sequence mutations are faithfully transmitted from one generation to the next in a mendelian pattern, epimutations do not involve changes in the DNA sequence and are relatively unstable, perhaps as a result of epigenetic reprogramming, in primordial germ cells and gametes,8 in the male genome in the zygote,9,10 and in the preimplantation embryo.11 This process removes and resets epigenetic marks between generations. Nevertheless, nonmendelian patterns of transgenerational epigenetic inheritance have been reported in mice.12-14 In the eight previously reported cases of germ-line MLH1 epimutation in humans, no intergenerational transmission was found, although in one patient the epimutation was reported in a low proportion of spermatozoa.4
Since the presence of an MLH1 epimutation in the germ line implies a potential for inheritance, we sought evidence for transmission between generations. In this study, we identified additional persons with germ-line MLH1 epimutations and in one family showed maternal transmission of the epimutation to her son but its erasure in his spermatozoa. Three other siblings from the two families we studied also inherited the affected maternal alleles, but in these cases the epimutation had reverted to the normal state, with concomitant allelic reactivation. These findings are consistent with germ-line transmission of a silent epigenetic state that confers disease susceptibility in humans.
Methods
Patients and Family Members
Our study was approved by the ethics committee at St. Vincent's Hospital in Sydney. Tissues were obtained with written informed consent from probands and family members at St. Vincent's Hospital and Women's and Children's Hospital in Adelaide, Australia.
We selected 24 patients in whom colorectal or endometrial cancer had developed before the age of 50 years and who lacked deleterious germ-line sequence mutations in MSH2 or MLH1. In each case, the tumors had microsatellite instability, with complete loss of MLH1 protein expression and retention of MSH2. Additional tissues were collected from patients shown to carry an MLH1 germ-line epimutation and from their first-degree relatives. The “swim-up” procedure was used to isolate motile spermatozoa.15 To remove contaminating somatic cells, spermatozoa that were used for DNA analyses were additionally sorted by flow cytometry (FACSVantage DiVa, Becton Dickinson).16 DNA was extracted from spermatozoa, hair follicles, and buccal mucosa with the use of QuickExtract solution (Epicentre Biotechnologies) and from peripheral-blood leukocytes with the use of phenol–chloroform.
Methylation Analyses
Methylation of the promoter of MLH1 (A and C regions) and of the EPM2AIP promoter on the opposite strand was identified with the use of combined bisulfite restriction analyses (Figure 1AFigure 1
Germ-Line Epimutation and Allelic Loss of Expression of MLH1 in Patients A and B.) and confirmed by allelic bisulfite sequencing.7 Quantitative real-time methylation-specific polymerase-chain-reaction (PCR) assays were performed on bisulfite-treated DNA with the use of primers specific to methylated templates for the C region of MLH1 and the imprinted SNRPN gene.17 Primers that amplify the control gene MyoD regardless of its methylation status were used to normalize for DNA input. Real-time methylation-specific PCR assays with iQ SYBR Green Supermix reagent were analyzed with the use of a real-time PCR system (MyiQ, BioRad). Absolute values for experimental samples were calculated from the PCR cycle number at which the fluorescence crossed the threshold with the use of a standard curve. The percentage of methylated alleles in the C region of MLH1 and SNRPN was calculated against MyoD with reference to 100% in vitro methylated human DNA (Chemicon).18 All primer sequences are available on request.
Haplotyping
Single-nucleotide polymorphism (SNP) typing was performed by PCR amplification of constitutional DNA followed by restriction digestion or direct sequencing of the purified amplicons. Markers of sequence-tagged sites were typed by PCR amplification with the use of fluorescent-labeled primers,19 separated by capillary electrophoresis on an automated DNA sequencer, and sized with the use of LIZ markers (ABI 3700, Applied Biosystems).
Allelic Expression
For each patient or family member, heterozygous polymorphisms within exons of MLH1 and EPM2AIP were used to identify the alleles being transcribed.20 RNA was extracted from peripheral-blood leukocytes, lymphoblastoid cells, and spermatozoa with the use of Trizol reagent (Invitrogen), treated with DNaseI, and converted to complementary DNA (cDNA). Allelic expression was determined by sequencing cDNA at I219V SNP within exon 8 (rs1799977) and at polymorphisms within exon 16 and EPM2AIP.
Results
By studying the peripheral blood of 24 patients, we identified two unrelated women (Patient A and Patient B) who had the typical molecular and clinical characteristics of persons with germ-line MLH1 epimutations — namely, multiple MLH1-negative cancers of the colorectum and endometrium and hemiallelic methylation of MLH1 in all somatic cells. In both women, there was dense methylation of one allele of the MLH1 and EPM2AIP promoters in somatic cells from the three embryonic germ layers (Figure 1B, and Fig. 1A of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Both women had metachronous carcinomas that had microsatellite instability and lacked MLH1 expression. (Patient A received a diagnosis of cancer of the endometrium at the age of 45 years, of the colon at 59 years, and of the rectum at 60 years; Patient B received a diagnosis of cancer of the colon at 41 years and of the rectum at 45 years.) Patient A was heterozygous for a SNP (rs1800734) within the MLH1 promoter, with methylation confined to the A allele. In both Patient A and Patient B, the methylated allele was transcriptionally silent, as evidenced by monoallelic expression of MLH1 and EPM2AIP transcripts in their messenger RNA (mRNA) (Figure 1C and 1D, and Fig. 1B of the Supplementary Appendix).
To identify MLH1 epimutations within families of the probands, combined bisulfite restriction analysis was performed on constitutional DNA from nine first-degree relatives, none of whom had a history of cancer (Figure 2B and 2CFigure 2
Pedigrees of Patients A and B Showing Intergenerational Transmission of the MLH1 Epimutation and Haplotypes.). Partial methylation of MLH1 was found in one of Patient A's four sons (family member II6-A) (Figure 2C). Methylation of the A allele (SNP rs1800734) on approximately 50% of chromosomes was confirmed by bisulfite sequencing (Figure 3AFigure 3
Maternal Inheritance of the MLH1 Germ-Line Epimutation by Family Member II6-A and the Erasure of the Epimutation in His Spermatozoa.). We identified an expressible C→T SNP within MLH1 exon 16 in family member II6-A, which was used to demonstrate that he was transcribing RNA only from the MLH1 allele inherited from his father (Figure 3A). These data are consistent with transmission of the MLH1 epimutation from Patient A to her son.To ascertain the possibility of transmission of the MLH1 epimutation from family member II6-A to his offspring, we studied the level of allelic methylation in his pure motile spermatozoa with the use of a sensitive quantitative real-time methylation-specific PCR assay within the C region of MLH1 (Figure 1A). In DNA from peripheral-blood leukocytes obtained from family member II6-A, approximately half of the MLH1 alleles (mean ±SD, 42.0±4.6%) were methylated. In contrast, his sperm had no trace of MLH1 methylation, despite containing equal proportions of alleles derived from his mother and father (Figure 3B). Furthermore, analysis of the RNA in his sperm at the MLH1 exon 16 C→T SNP showed reactivation of the maternally derived MLH1 allele (Figure 3B). These results indicate reversion of the MLH1 epimutation to normality during spermatogenesis, suggesting a negligible risk of transmission from family member II6-A (Figure 4Figure 4
Schematic Representation of Inheritance of MLH1 Alleles in Three Sons of Patient A.).To investigate allelic inheritance patterns and the possibility that the epimutations were caused by alterations in the DNA strand carrying the allele that could influence methylation of the allele (in cis defects), we used SNPs within MLH1, EPM2AIP, and flanking sequence-tagged site markers to construct a haplotype map of a region of approximately 8 Mb around MLH1 for all members of both families (Figure 2B and 2C, and Fig. 2 of the Supplementary Appendix). Patient A, her sister (family member I1-A), and three of her four sons (family members II5-A, II6-A, and II7-A) all shared a haplotype in this region, even though MLH1 was methylated only in Patient A and her son (family member II6-A). In the case of Patient B, haplotype and expression analysis (Figure 2B, and Fig. 1 of the Supplementary Appendix) confirmed that the MLH1 epimutation resided on her maternally derived allele. This is likely to have arisen spontaneously, since we found no evidence of methylation in her mother (Figure 2B). Notably, the haplotype in Patient B differed from the one on which the epimutation occurred in Patient A's family. Patient B transmitted the haplotype to one of her two sons (family member III2-B), but there was no evidence of MLH1 methylation in his case (Figure 2B). For both family member II5-A and family member III2-B, absence of methylation from their respective maternal alleles correlated with biallelic expression from the MLH1 locus (Fig. 3 of the Supplementary Appendix), indicating reversion of the epimutation in these family members or in their mothers' germ cells. No recombinations were observed in the vicinity of MLH1, indicating that the affected alleles were identical in family members bearing the epimutation and in those in whom it had reverted (Fig. 2 of the Supplementary Appendix).
Epimutations are meiotically reversible and often show somatic mosaicism. We therefore considered whether some family members had low levels of allelic MLH1 methylation, suggesting incomplete somatic erasure of an epimutation, or a susceptibility of the allele to subsequent somatic methylation. With the use of real-time methylation-specific PCR, we found no evidence of allelic mosaicism for MLH1 methylation in any patient in our study, except those with epimutations (38±9% for Patient B, 42±7% for Patient A, and 42±4.6% for family member II6-A).
Discussion
We have found evidence of germ-line epimutation of MLH1 in a woman with cancer and in her son (Figure 4), which supports the concept of transgenerational epigenetic inheritance. The MLH1 epimutation that predisposed the mother to multiple tumors with microsatellite instability has increased the risk of cancer in her son (family member II6-A).
The findings from the two families in this study, as well as previous studies, offer insights into the pattern of inheritance of germ-line epimutations. With reference to the parent of origin, the mother of family member II6-A, like the mothers of two patients with MLH1 epimutations reported previously, had cancer in a pattern typical of hereditary nonpolyposis colorectal cancer.6 Furthermore, in two other cases in which germ-line epimutations were shown to arise spontaneously (Patient B and a patient whose case was reported previously7), the methylated allele was maternally derived. Taken together, these data raise the possibility that epigenetic errors may arise more frequently during oogenesis or are more likely to be maintained during this process. Our finding of erasure of the epimutation during spermatogenesis in family member II6-A is consistent with this hypothesis. However, paternal inheritance cannot be excluded, given our previous finding of low-level MLH1 methylation in sperm of an affected person.6
Another characteristic of the inheritance pattern in the families in this study is that four sons inherited their mother's MLH1 haplotype, yet in three of the sons, the maternally derived allele had undergone demethylation and transcriptional reactivation. It appears that the normal process of gametogenesis allowed correction of the MLH1 epimutation, perhaps contemporaneously with erasure of parent-specific methylation of imprinted genes in primordial germ cells.11 If so, then transmission of an epimutation to family member II6-A must reflect resistance to reprogramming, either through incomplete erasure or by retention of an epigenetic memory. Although at present we have limited information, the overall cancer risk for families with germ-line MLH1 epimutations appears to be lower than for those with germ-line sequence mutations.
An alternative explanation for our findings is that epimutations are not inherited per se. Rather, they are erased in gametogenesis but reestablished in successive generations because of cis-acting or even trans-acting genetic factors that increase susceptibility to MLH1 epimutations.21,22 Examples of epigenetic silencing that are driven by genetic events in cis include deletion of imprint-control centers in imprinted disorders23 and expansion of triplet repeats within the FMR1 promoter in the fragile X syndrome.24 Such a mechanism may also explain the recently reported strongly heritable pattern of epimutation in MSH2, 25 since the methylation state segregated faithfully with the genetic haplotype. In contrast, in the two families described in our study, we found no evidence of a fully penetrant in cis defect. Rather, they showed epimutations that were meiotically reversible and transmitted in a nonmendelian fashion. A simple explanation for this pattern is that epimutations can occur on any haplotype, and although they usually are cleared in the germ line, they may be retained at low but uncertain frequency.
Regardless of uncertainties about patterns, frequencies, and mechanisms of inheritance, offspring of patients with MLH1 epimutations must be regarded as being at risk for cancer until proven otherwise. The broader implication of this study is that disease states in humans may be the consequence of nonmendelian inheritance of epigenetic changes in one or more genes.
Supported by the National Health and Medical Research Council, the Cancer Council New South Wales, and the Justin O'Connor Foundation. Mr. Wong is the recipient of a University of New South Wales International Postgraduate Research Scholarship.
No potential conflict of interest relevant to this article was reported.
We thank Kay Fong Cheong, Deborah Packham, Vita Ap Lin, and Chau-To Kwok for their technical assistance and Rachel Williams and Kerry Phillips for their coordination of sample collection.
Source Information
From the Department of Medical Oncology, St. Vincent's Hospital (M.P.H., J.J.L.W., C.M.S., R.L.W.); the Schools of Medicine (M.P.H., C.M.S., R.L.W.) and Medical Sciences (J.J.L.W., N.J.H.), University of New South Wales; and the Victor Chang Cardiac Research Institute (C.M.S., D.I.K.M.) — all in Sydney; the Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, Australia (G.S.); and the Children's Hospital Oakland Research Institute, Oakland, CA (D.I.K.M.).
Address reprint requests to Dr. Ward at the Department of Medical Oncology, St. Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia, or at robyn@unsw.edu.au.
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