Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles

Bruder, Carl E.G.; Piotrowski, Arkadiusz; Gijsbers, Antoinet A.C.J.; Andersson, Robin; Erickson, Stephen W.; Ståhl, Teresita Díaz de; Menzel, Uwe; Sandgren, Johanna; Tell, Désirée von; Poplawski, Andrzej; Crowley, Michael R.; Crasto, Chiquito J.; Partridge, E. Christopher; Tiwari, Hemant K.; Allison, David B.; Komorowski, Jan; Ommen, Gert‐Jan B. van; Boomsma, Dorret I.; Pedersen, Nancy L.; Dunnen, Johan T. den; Wirdefeldt, Karin; Dumanski, Jan P.

doi:10.1016/j.ajhg.2007.12.011

Cited by 532 publications

(377 citation statements)

References 34 publications

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“…The motivation for this study stems from our previous analysis of genetic variation and genetic heterogeneity in somatic cells, both for normal and tumor-derived samples. [15][16][17] One of our previous reports, surveying B1% of the human genome, suggested a frequent intratumoral (within the same primary tumor) heterogeneity of genetic aberrations in breast cancer. 15 We therefore hypothesized that there likely exist differences between the genetic profiles of primary tumors and corresponding metastases from the same patient.…”

Section: Introductionmentioning

confidence: 99%

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

et al. 2010

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Breast cancer is a major cause of morbidity and mortality in women and its metastatic spread is the principal reason behind the fatal outcome. Metastasis-related research of breast cancer is however underdeveloped when compared with the abundant literature on primary tumors. We applied an unexplored approach comparing at high resolution the genomic profiles of primary tumors and synchronous axillary lymph node metastases from 13 patients with breast cancer. Overall, primary tumors displayed 20% higher number of aberrations than metastases. In all but two patients, we detected in total 157 statistically significant differences between primary lesions and matched metastases. We further observed differences that can be linked to metastatic disease and there was also an overlapping pattern of changes between different patients. Many of the differences described here have been previously linked to poor patient survival, suggesting that this is a viable approach toward finding biomarkers for disease progression and definition of new targets useful for development of anticancer drugs. Frequent genetic differences between primary tumors and metastases in breast cancer also question, at least to some extent, the role of primary tumors as a surrogate subject of study for the systemic disease.

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Section: Introductionmentioning

confidence: 99%

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

et al. 2010

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“…6 However, intra-twin pair variability for germ-line CNVs could not be detected in our subset of EA and CDH MZ twins. Within the limitations of the used experimental approach, structural variants in mosaic form (above 20%) could neither be demonstrated.…”

Section: Discussionmentioning

confidence: 62%

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

et al. 2011

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The occurrence of phenotypic differences between monozygotic (MZ) twins is commonly attributed to environmental factors, assuming that MZ twins have a complete identical genetic make-up. Yet, recently several lines of evidence showed that both genetic and epigenetic factors could have a role in phenotypic discordance after all. A high occurrence of copy number variation (CNV) differences was observed within MZ twin pairs discordant for Parkinson's disease, thereby stressing on the importance of post-zygotic mutations as disease-predisposing events. In this study, the prevalence of discrepant CNVs was analyzed in discordant MZ twins of the Esophageal Atresia (EA) and Congenital Diaphragmatic Hernia (CDH) cohort in the Netherlands. Blood-derived DNA from 11 pairs (7 EA and 4 CDH) was screened using high-resolution SNP arrays. Results showed an identical copy number profile in each twin pair. Mosaic chromosome gain or losses could not be detected either with a detection threshold of 20%. Some of the germ-line structural events demonstrated in five out of eleven twin pairs could function as a susceptible genetic background. For example, the 177-Kb loss of chromosome 10q26 in CDH pair-3 harbors the TCF7L2 gene (Tcf4 protein), which is implicated in the regulation of muscle fiber type development and maturation. In conclusion, discrepant CNVs are not a common cause of twin discordancy in these investigated congenital anomaly cohorts.

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“…Epigenetic differences have been demonstrated in MZ twins discordant for schizophrenia and in twin pairs discordant for birth weight and differences in the methylation of the COMT gene promoter region [Petronis et al, 2003;Mill et al, 2006]. Additionally, Bruder et al [2008] recently reported that MZ twin pairs who were discordant for Parkinson disease showed differences in copy number variants on genetic microarray testing. These are areas which may be of value for future exploration in NF1.…”

Section: Discussionmentioning

confidence: 99%

Variable expression of neurofibromatosis 1 in monozygotic twins

Rieley

Stevenson

Viskochil

et al. 2011

American J of Med Genetics Pt A

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Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P C ) for each feature. MZ twins were highly concordant in numbers of cafe-au-lait spots (P C ¼ 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P C ¼ 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second -hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P C ¼ 0.80). Three sets of twins were discordant for scoliosis (P C ¼ 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.

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Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles

Cited by 532 publications

References 34 publications

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

Variable expression of neurofibromatosis 1 in monozygotic twins

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