X-inactivation patch size in human female tissue confounds the assessment of tumor clonality

Novelli, Marco; Cossu, Antonio; Oukrif, Dahmane; Quaglia, Alberto; Lakhani, Sunil R.; Poulsom, Richard; Sasieni, Peter; Carta, Piera; Contini, M; Pasca, A; Palmieri, Giuseppe; Bodmer, W F; Tanda, Francesco; Wright, Nicholas

doi:10.1073/pnas.0437825100

Cited by 116 publications

(90 citation statements)

References 20 publications

(14 reference statements)

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“…First, for the genetic analysis, we pooled the bulk of the cyst-lining epithelium from each specimen to avoid the bias introduced by the X-inactivation patch size in the assessment of clonality. 42 It is possible that clonal proliferation occurs only focally in some cystadenomas and that the molecular changes in these foci occur in the absence of morphologic alterations that are not detected microscopically. Second, our results do not exclude the possibility that multiple independent clonal events occur in a cyst, which would then result in the erroneous impression of polyclonality.…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic analysis of ovarian serous cystadenomas

Cheng

Kurman

Wang

et al. 2004

Laboratory Investigation

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Ovarian serous cystadenomas are common ovarian lesions that may be precursors of serous borderline tumors, which can in turn progress to low-grade serous carcinomas. It has been shown that low-grade serous carcinoma and serous borderline tumors are characterized by frequent mutations in BRAF or KRAS genes, but the mutational status of these genes in serous cystadenomas and the clonal nature of serous cystadenomas have not been fully investigated. We isolated cyst-lining epithelium from 30 consecutive serous cystadenomas, and analyzed their BRAF and KRAS mutational status. Wild-type sequences of BRAF and KRAS were detected in all specimens. Using the human androgen receptor gene as a polymorphic marker, we also examined the clonal status of epithelial cells in all of the serous cystadenomas. Four of 29 (14%) informative specimens were monoclonal based on the methylation pattern. These monoclonal cystadenomas were significantly (Po0.01) larger in size (48 cm) than the nonclonal cystadenomas. These data indicate that serous cystadenomas do not contain mutations in either BRAF or KRAS genes and that most serous cystadenomas are polyclonal. Accordingly, it appears that serous cystadenomas develop as a hyperplastic expansion from epithelial inclusions with a clonal/neoplastic transformation occurring in a subset of them.

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Section: Discussionmentioning

confidence: 99%

Molecular genetic analysis of ovarian serous cystadenomas

Cheng

Kurman

Wang

et al. 2004

Laboratory Investigation

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“…We have previously shown that the adult colon has large families of adjacent crypts (Ϸ450) (15), which show the same X-linked gene, indicating that after lyonization, early stem cells from the colonic mucosal crypts expand, implicitly by crypt fission, to form large families of related crypts, so far as sharing the same X-chromosome is concerned. However, Kim and Shibata results (17,18) show that the methylation patterns of adjacent crypts diverge markedly by stem cell niche succession, but every 8 years or so, a ''bottleneck'' is reached, where all stem cells in the crypt are closely related.…”

Section: Discussionmentioning

confidence: 99%

“…This proposal would predict that neighboring colonic crypts are closely related to each other. We have previously shown that the X-linked patch in the adult human colon is large, Ϸ450 crypts, so colonic crypts can develop into large families (15). But this does not tell us anything about the development and spread of mutations occurring later in life.…”

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confidence: 99%

“…Such conversion has previously been shown in mice that have DNA mutations in nuclear housekeeping genes such as G6PD and metallothionein induced by ethylnitrosourea (11,12). Colonic crypts in mice (13) and humans (14)(15)(16) are clonal populations; we have shown that one of a number of colonic stem cells can acquire a mutation in the mitochondrial genome, resulting in detectable cytochrome c oxidase deficiency only after the age of 40.…”

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Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission

Greaves

Preston

Tadrous

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The understanding of the fixation of mutations within human tissues and their subsequent clonal expansion is a considerable problem, of which little is known. We have previously shown that nononcogenic mutations in the mitochondrial genome occur in one of a number of morphologically normal colonic crypt stem cells, the progeny of which later occupy the whole crypt. We propose that these wholly mutated crypts then clonally expand by crypt fission, where each crypt divides into two mutated daughter crypts. Here we show that (i) mutated crypts in the process of fission share the same mutated mitochondrial genotype not present in neighboring cytochrome c oxidase-positive crypts (the odds of this being a random event are >2.48 ؋ 10 9 :1); (ii) neighboring mutated crypts have the same genotype, which is different from adjacent cytochrome c oxidase-positive crypts; (iii) mutated crypts are clustered together throughout the colon; and (iv) patches of cytochrome c oxidase-deficient crypts increase in size with age. We thus demonstrate definitively that crypt fission is the mechanism by which mutations spread in the normal human colon. This has important implications for the biology of the normal adult human colon and possibly for the growth and spread of colorectal neoplasms.fission ͉ mitochondria

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“…The clonality of normal and neoplastic tissue is assessed by the analysis of patches in chimeras or mosaics heterotypic for a clonal lineage marker. The ability to detect polyclonality in early human tumors is restricted by the large patch sizes of X-inactivation mosaics (4). The first indication that familial intestinal adenomas were commonly polyclonal in structure came from a study of a mosaic XY 7 XO male patient with familial adenomatous polyposis (5).…”

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Polyclonality of familial murine adenomas: Analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions

Thliveris

Halberg

Clipson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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In previous studies demonstrating the polyclonal structure of familial intestinal adenomas, high tumor multiplicity made it difficult to eliminate the possibility that polyclonality arose by the random collision of distinct initiated clones as opposed to some form of clonal interaction. We sought to test further the random collision hypothesis. Chimeric mice carrying the multiple intestinal neoplasia (Min) mutation of the adenomatous polyposis coli gene (Apc) and homozygous for the tumor resistance allele of the Mom1 locus were established. These chimeras also display a strong propensity for tumors of polyclonal structure, despite their markedly reduced tumor multiplicity. Considering tumor sizes and multiplicities, the observed fraction of overtly polyclonal heterotypic adenomas was significantly higher than predicted by the random collision hypothesis. This finding supports models of polyclonality involving interaction among multiple initiated clones. The extent of clonal interaction was assessed by statistical analyses that relate the observed frequency of overtly polyclonal heterotypic tumors to the geometry of the chimeric patches and the pattern of underlying crypts. These statistical calculations indicate that the familial adenomas of the Apc Min/؉ mouse may commonly form through interactions between clones as close as 1-2 crypt diameters apart.Bayesian image reconstruction ͉ clonal interactions ͉ colon cancer ͉ spatial statistics ͉ tumorigenesis M ost current models of tumorigenesis involve a monoclonal origin. The evidence for monoclonality at the earliest stages of spontaneous intestinal neoplasia is limited. Intestinal adenomas and carcinomas in carcinogen-treated mice (1, 2) and large adenomas in humans (3) seem to be monoclonal. The clonality of normal and neoplastic tissue is assessed by the analysis of patches in chimeras or mosaics heterotypic for a clonal lineage marker. The ability to detect polyclonality in early human tumors is restricted by the large patch sizes of X-inactivation mosaics (4). The first indication that familial intestinal adenomas were commonly polyclonal in structure came from a study of a mosaic XY 7 XO male patient with familial adenomatous polyposis (5). In that study, 5% of microadenomas were found to have a mixed karyotype, which led the authors to suggest that as many as 76% are polyclonal (ref. was compromised by high tumor multiplicity. In the latter case, it was estimated that a model of passive clonal interaction could explain the overall frequency of heterotypic adenomas if the intestinal epithelium is heterogeneous with only a portion of the tissue susceptible to tumorigenesis. Regional heterogeneity could involve exposure to dietary carcinogens. Indeed, recent studies have found that adenomas in B6 Min mice form predominantly in the distal segment of the small intestine (9). We have therefore assessed the incidence of heterotypic tumors in chimeric Min mice in which the tumor multiplicity has been strongly reduced by homozygosity for the resistance allele of the...

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X-inactivation patch size in human female tissue confounds the assessment of tumor clonality

Cited by 116 publications

References 20 publications

Molecular genetic analysis of ovarian serous cystadenomas

Molecular genetic analysis of ovarian serous cystadenomas

Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission

Polyclonality of familial murine adenomas: Analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions

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