DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Esteller, Manel; Fraga, Mario F.; Guo, Mingzhou; Garcı́a-Foncillas, Jesús; Hedenfalk, Ingrid; Godwin, Andrew K.; Trojan, Joerg; Vaurs‐Barrière, Catherine; Bignon, Yves Jean; Ramus, Susan J.; Benı́tez, Javier; Caldés, Trinidad; Akiyama, Yoshimitsu; Yuasa, Y; Launonen, Virpi; Cañal, María Jesús; Rodrı́guez, Roberto; Capellà, Gabriel; Peinado, Miguel A.; Borg, Åke; Aaltonen, Lauri A.; Ponder, Bruce A.J.; Baylin, Stephen B.; Herman, James G.

doi:10.1093/hmg/10.26.3001

Cited by 404 publications

(288 citation statements)

References 35 publications

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“…This is based on the observation of an inverse association between LOH and hypermethylation, indicating that a singly retained allele (which carries the germline mutation) is not hypermethylated, whereas in tumors with both alleles retained the wt copy occasionally is in 0-46% of tumors Kuismanen et al, 2000;Wheeler et al, 2000;Esteller et al, 2001;Potocnik et al, 2001). The proportion of tumors showing MLH1 promoter methylation in the present study (4/55, 7.3%) was slightly lower than in some studies cited above, which may reflect the different regions of the MLH1 promoter studied, or different techniques or thresholds used to detect methylation.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P ¼ 0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, Po0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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“…However, it is known that TSG inactivation may be an early event in tumorigenesis. Thus, methylation may be the 'second hit' in familial cancer syndrome tumours (Prowse et al, 1997, Esteller et al, 2001b. Furthermore, in sporadic and familial adenomatous polyposis coli, TSG CpG island methylation may be detected in the earliest precursor lesion in colorectal carcinogenesis, aberrant crypt foci (Chan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

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“…We took into account only the cases for which we were certain about the pathogenicity of the variant: cases 1-16, which were positive for a deleterious mutation in the BRCA genes and cases 30 -48, which were not associated with BRCA and in which a common polymorphism was used for LOH analysis. For this analysis, we included 23 BRCA1-positive cases from different European and American groups, reported by Esteller et al, 22 which were not included in our series and from which 21 showed loss of the wild-type allele in the tumor. Comparing the previous information we had from these variants and the results obtained by LOH analysis, the sensitivity of the test was 92.3% (IC95% ϭ 83.9 -100%) and the specificity 94.4% (IC95% ϭ 83.9 -100%).…”

Section: Sensitivity and Specificity Of The Testmentioning

confidence: 99%

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Osorio

Hoya

Rodríguez‐López

et al. 2002

Intl Journal of Cancer

108

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The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor supressors and it is beleived that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to highrisk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes.

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DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis

Cited by 404 publications

References 35 publications

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

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