Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma

Vukovic, Bisera; Park, Paul C.; Al-Maghrabi, Jaudah; Beheshti, Ben; Sweet, Joan; Evans, Angela; Trachtenberg, John; Squire, Jeremy A.

doi:10.1038/sj.onc.1206227

Cited by 77 publications

(54 citation statements)

References 55 publications

(47 reference statements)

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“…Telomeres in tumor cells are different from telomeres in normal cells; they are generally shorter, even critically short [Vukovic et al, 2003;Meeker et al, 2004]. However, they may also be elongated or different subpopulations of telomere lengths may be present [Meeker et al, 2004].…”

Section: Telomere Organization In Tumor Cellsmentioning

confidence: 97%

The significance of telomeric aggregates in the interphase nuclei of tumor cells

Mai

Garini

2006

J of Cellular Biochemistry

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Section: Telomere Organization In Tumor Cellsmentioning

confidence: 97%

The significance of telomeric aggregates in the interphase nuclei of tumor cells

Mai

Garini

2006

J of Cellular Biochemistry

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“…In high-grade PIN, telomeres are also short in the vast majority of cases (40,41). Interestingly, Vukovic and colleagues found that PIN lesions near carcinoma often showed shorter telomeres than PIN lesions away from carcinoma (41).…”

Section: Molecular Biology Of Pinmentioning

confidence: 99%

Premalignancy in Prostate Cancer: Rethinking What We Know

Marzo

Haffner

Lotan

et al. 2016

Cancer Prevention Research

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High-grade prostatic intraepithelial neoplasia (PIN) has been accepted as the main precursor lesion to invasive adenocarcinoma of the prostate, and this is likely to be the case. However, in an unknown number of cases, lesions fulfilling the diagnostic criteria for high-grade PIN may actually represent intra-acinar or intraductal spread of invasive carcinoma. Intriguingly, this possibility would not contradict many of the findings of previous epidemiologic studies linking high-grade PIN to carcinoma or molecular pathologic studies showing similar genomic (e.g., TMPRSS2-ERG gene fusion) as well as epigenomic and molecular phenotypic alterations between high-grade PIN and carcinoma. Also, this possibility would be consistent with previous anatomic studies in prostate specimens linking high-grade PIN and carcinoma in autopsy and other whole prostate specimens. In addition, if some cases meeting morphologic criteria for PIN actually represent intra-acinar spread of invasive carcinoma, this could be an important potential confounder of the interpretation of past clinical trials enrolling patients presumed to be without carcinoma, who are at high risk of invasive carcinoma. Thus, in order to reduce possible bias in future study/trial designs, novel molecular pathology approaches are needed to decipher when an apparent PIN lesion may be intra-acinar/intra-ductal spread of an invasive cancer and when it truly represents a precursor state. Similar approaches are needed for lesions known as intraductal carcinoma to facilitate better classification of them as true intra-ductal/acinar spread on one hand or as precursor highgrade PIN (cribriform type) on the other hand; a number of such molecular approaches (e.g., coevaluating TMPRSS-ERG fusion and PTEN loss) are already showing excellent promise.Cancer Prev Res; 9(8); 648-56. Ó2016 AACR.

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“…10 This difference in rearrangements is at the origin of chromosomal evolution seen in many complex tumors that exhibit dynamic BBF cycles, such as osteosarcoma, and prostate, breast and colon cancer. [14][15][16][17][18][19][20][21] Aberrations in centrosome duplication cycles leading to centrosome amplification have been observed in many different cancers 22,23 and are another characteristic feature of RS cells. 1,[24][25][26] Thus due to the combination of telomere dysfunction, centrosome amplification and defective spindle formation, RS cells are expected to gain increasingly complex karyotypes with respect to their chromosome numbers, rearrangements and nuclear distribution among individual sub-nuclei of the multi-nucleated RS cell.…”

Section: Introductionmentioning

confidence: 99%

Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles

Guffei¹,

Sarkar²,

Klewes³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHodgkin's lymphoma is characterized by the presence of mono-nucleated Hodgkin cells and bi-to multi-nucleated Reed-Sternberg cells. We have recently shown telomere dysfunction and aberrant synchronous/asynchronous cell divisions during the transition of Hodgkin cells to Reed-Sternberg cells. 1 Design and MethodsTo determine whether overall changes in nuclear architecture affect genomic instability during the transition of Hodgkin cells to Reed-Sternberg cells, we investigated the nuclear organization of chromosomes in these cells. ResultsThree-dimensional fluorescent in situ hybridization revealed irregular nuclear positioning of individual chromosomes in Hodgkin cells and, more so, in Reed-Sternberg cells. We characterized an increasingly unequal distribution of chromosomes as mono-nucleated cells became multi-nucleated cells, some of which also contained chromosome-poor 'ghost' cell nuclei. Measurements of nuclear chromosome positions suggested chromosome overlaps in both types of cells. Spectral karyotyping then revealed both aneuploidy and complex chromosomal rearrangements: multiple breakage-bridge-fusion cycles were at the origin of the multiple rearranged chromosomes. This conclusion was challenged by super resolution three-dimensional structured illumination imaging of Hodgkin and Reed-Sternberg nuclei. Three-dimensional super resolution microscopy data documented inter-nuclear DNA bridges in multi-nucleated cells but not in mono-nucleated cells. These bridges consisted of chromatids and chromosomes shared by two Reed-Sternberg nuclei. The complexity of chromosomal rearrangements increased as Hodgkin cells developed into multi-nucleated cells, thus indicating tumor progression and evolution in Hodgkin's lymphoma, with Reed-Sternberg cells representing the highest complexity in chromosomal rearrangements in this disease. ConclusionsThis is the first study to demonstrate nuclear remodeling and associated genomic instability leading to the generation of Reed-Sternberg cells of Hodgkin's lymphoma. We defined nuclear remodeling as a key feature of Hodgkin's lymphoma, highlighting the relevance of nuclear architecture in cancer.Key words: 3D nucleus, chromosomal rearrangements, SKY, 3D-SIM, BBF-cycles, ReedSternberg cells.Citation: Guffei A, Sarkar R, Klewes L, Righolt C, Knecht H, and Mai S. Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles. Haematologica 2010;95(12):2038-2046. doi:10.3324/haematol.2010 Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles © F e r r a t a S t o r t i F o u n d a t i o n

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Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma

Cited by 77 publications

References 55 publications

The significance of telomeric aggregates in the interphase nuclei of tumor cells

The significance of telomeric aggregates in the interphase nuclei of tumor cells

Premalignancy in Prostate Cancer: Rethinking What We Know

Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles

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