Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe.

Fey, Martin F.; Peter, H J; Hinds, Heather L.; Zimmermann, Arthur; Liechti‐Gallati, Sabina; Gerber, H; Studer, H; Tobler, Andreas

doi:10.1172/jci115733

Cited by 94 publications

(58 citation statements)

References 35 publications

(28 reference statements)

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“…Recently, Gale et al 29 found significant NRXI in blood-derived cells in 23% of normal females using PGK and HPRT probes and 22% of females using M27␤, 30 which has been confirmed in numerous other studies. [33][34][35][36] Discordance in the incidence of NRXI was initially explained by the diversity of assays used, the different criteria for NRXI, and the small population sizes. However, a more plausible explanation came from studies that analyzed Xinactivation patterns of different tissues in the same female.…”

Section: Study Of the Normal Female Population: Unequal Lyonization Rmentioning

confidence: 99%

“…However, a more plausible explanation came from studies that analyzed Xinactivation patterns of different tissues in the same female. For example, Fey et al 33 reported that the incidence of NRXI was low in gastrointestinal mucosa and thyroid tissue, but was significantly higher in blood cells. Gale et al 31 reported that 45% of females analyzed have different patterns of X-inactivation when blood-derived cells were compared to muscle and skin samples.…”

Section: Study Of the Normal Female Population: Unequal Lyonization Rmentioning

confidence: 99%

See 1 more Smart Citation

X-inactivation analysis in the 1990s: promise and potential problems

Busque

Gilliland

1998

Leukemia

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Section: Study Of the Normal Female Population: Unequal Lyonization Rmentioning

confidence: 99%

Section: Study Of the Normal Female Population: Unequal Lyonization Rmentioning

confidence: 99%

X-inactivation analysis in the 1990s: promise and potential problems

Busque

Gilliland

1998

Leukemia

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“…For example, assessment of clonality by X-inactivation analysis is based on inactivation of either the paternal or the maternal X-chromosome copy in a given cell and thus represents a marker which preexists in early transformed founder cells of malignant tumours, since X-inactivation patterns in particular cells or tissues are established in early embryogenesis. Therefore, clonal X-inactivation analysis provides insight into an early phase of carcinogenesis and represents an 'early marker' of the clonal relation of different tumour lesions [28]. If a marker captures a 'late' genetic event, it is conceivable that separate tumour lesions in an organ show disparate patterns whilst still being clonally related by virtue of sharing identical X-inactivation patterns.…”

Section: Multiple Tumour Lesions In An Organ: Derived From One or Sevmentioning

confidence: 99%

“…We looked at this problem in a series of gastro-intestinal cancers taken from female patients whereby several geographically distinct tumour areas were examined with a battery of clinically relevant molecular markers [39]. The question of whether these tumours had arisen from one or perhaps a few single mucosal founder cells was tackled by clonal X-inactivation analysis [28]. Each tumour (with one exception) showed a uniform clonal X-inactivation pattern throughout all of the samples, suggesting the cancer's origin in a single early mucosal founder cell.…”

Section: Multiple Tumour Lesions In An Organ: Derived From One or Sevmentioning

confidence: 99%

Tumour heterogeneity and clonality – an old theme revisited

Fey¹,

Tobler²

1996

Annals of Oncology

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“…Activation by RAS of the RAL guanine nucleotide exchange factor is responsible for dampening the G 2 arrest induced by ethyl methanesulfonate in p53-deficient MDAH041 fibroblasts (24). On the other hand, activation of the RAS downstream effectors MEK2 3 and ERK are required for exit from DNA damage-induced G 2 cell cycle arrest (25) and the transition from G 2 into M (26,27), respectively.…”

mentioning

confidence: 99%

Oncogenic RAS Induces Accelerated Transition through G2/M and Promotes Defects in the G2 DNA Damage and Mitotic Spindle Checkpoints

Knauf

Ouyang

Knudsen

et al. 2006

Journal of Biological Chemistry

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Activating mutations of RAS are prevalent in thyroid follicular neoplasms, which commonly have chromosomal losses and gains. In thyroid cells, acute expression of HRAS V12 increases the frequency of chromosomal abnormalities within one or two cell cycles, suggesting that RAS oncoproteins may interfere with cell cycle checkpoints required for maintenance of a stable genome. To explore this, PCCL3 thyroid cells with conditional expression of HRAS V12 or HRAS V12 effector mutants were presynchronized at the G 1 /S boundary, followed by activation of expression of RAS mutants and release from the cell cycle block. Expression of HRAS V12 accelerated the G 2 /M phase by ϳ4 h and promoted bypass of the G 2 DNA damage and mitotic spindle checkpoints. Accelerated passage through G 2 /M and bypass of the G 2 DNA damage checkpoint, but not bypass of the mitotic spindle checkpoint, required activation of mitogen-activated protein kinase (MAPK). However, selective activation of the MAPK pathway was not sufficient to disrupt the G 2 DNA damage checkpoint, because cells arrested appropriately in G 2 despite conditional expression of HRAS V12,S35 or BRAF V600E . By contrast to the MAPK requirement for radiation-induced G 2 arrest, RAS-induced bypass of the mitotic spindle checkpoint was not prevented by pretreatment with MEK inhibitors. These data support a direct role for the MAPK pathway in control of G 2 progression and regulation of the G 2 DNA damage checkpoint. We propose that oncogenic RAS activation may predispose cells to genomic instability through both MAPK-dependent and independent pathways that affect critical checkpoints in G 2 /M.Human tumors, including those of the thyroid (1-3), arise from a single transformed cell. Despite their clonal origin, cells from advanced carcinomas are often genetically heterogeneous. Tumor cell variability is thought to result from genomic instability. Clonal heterogeneity in turn tends to predict a poor outcome and resistance to therapy. This is also the case in thyroid cancer. In thyroid tumors, the nature of the oncogenic events involved in the initiation of the neoplastic clone may determine the likelihood of genomic instability occurring at a later stage. Among the various forms of thyroid neoplasia, follicular adenomas and carcinomas are commonly aneuploid, whereas abnormalities in chromosome number are comparatively less frequent in papillary thyroid carcinomas. Mutations of all three RAS genes are found in benign and malignant follicular neoplasms and in follicular variant papillary thyroid carcinomas and are believed to be one of the early steps in thyroid tumor formation (4 -9). By contrast, rearrangements of the tyrosine kinase receptor gene RET (rearranged by transfection; RET/ PTC) are only found in papillary thyroid carcinomas, which are commonly diploid and less aggressive. A possible explanation for this is that activating mutations of RAS, but not of RET, promote tumor progression in part by decreasing genomic stability. Consistent with this is the observation that ...

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Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe.

Abstract: IntroductionThe clonality of human tumors can be studied by X inactivation/methylation analysis in female patients heterozygous for X-linked DNA polymorphisms. We present a detailed study on

Cited by 94 publications

References 35 publications

X-inactivation analysis in the 1990s: promise and potential problems

X-inactivation analysis in the 1990s: promise and potential problems

Tumour heterogeneity and clonality – an old theme revisited

Oncogenic RAS Induces Accelerated Transition through G2/M and Promotes Defects in the G2 DNA Damage and Mitotic Spindle Checkpoints

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