Genome Wide Screening of CAG Trinucleotide Repeat Lengths in Breast Cancer

Trinucleotide repeat sequences are widely present in the human genome. The expansion of CAG repeats have been studied very extensively, and shown to be the causative mechanism of more than 40 neuromuscular and neurodegenerative diseases. In the present study, we performed a genome wide screening of CAG repeat expansions in non-neoplastic tissues of 212 breast cancer cases and 196 healthy population controls using the Repeat Expansion Detection (RED) method. Distribution of CAG repeat lengths in cases was not significantly different from controls. However, dramatically expanded CAG repeats were detected in 2.4% (n= 5) of breast cancer cases where no repeats of similar size were detected in any of the healthy population controls. Although this trend shows only borderline significance (p= 0.06), this finding suggests a potential involvement of CAG repeat expansion in breast cancer susceptibility. These repeats may potentially affect the function of cancer predisposition genes, with a similar mechanism as in neurodegenerative and neuromuscular disorders.

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Screening A Trinucleotide Repeat Expansion: How precise PCR can be?

BioScientia Medicina ◽

10.32539/bsm.v3i3.94 ◽

2019 ◽

Vol 3 (3) ◽

pp. 34-40

Author(s):

Ziske Maritska ◽

Baharudin Baharudin ◽

Ardy Santosa ◽

Ching Leng Kee ◽

Tan Yue Ming ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Trinucleotide Repeat ◽

Repeat Expansion ◽

Cag Repeat ◽

Cag Repeats ◽

Chain Reaction ◽

Trinucleotide Repeat Expansion ◽

Pcr Method ◽

The Mean ◽

Polymerase Chain

ABSTRACT Background. Trinucleotide Repeat Expansion (TRE) in human DNA could lead to various diseases. An expanded CAG repeat (>31 or 37 repeats, depends on the ethnicity) in Androgen Receptor gene is suggested to be associated with the occurrence of isolated hypospadias. In an effort to identify the exact numbers of repeats, sequencing has been the most favored method to be conducted despite its cost. Objective. This study wished to investigate the possibilities of using Polymerase Chain Reaction (PCR) method to screen expanded repeats in isolated hypospadias, as one of the TRE diseases. Materials and Methods. Numbers of CAG repeat in twelve hypospadias patients and one normal male was first predicted from the visualization of PCR products in 3% agarose gel electrophoreses with 20 bp ladder marker before it was finally sequenced. Results. Two samples gave the same exact result, while the rest showed a range of 1-11 bp differences. Statistically, there was a significant difference between the mean of CAG repeats from PCR method (M=26.1667, SD=6.71272) and the mean of CAG repeats from sequencing (M=23.75, SD=5.70685); t(11)= 4.570, p=0.001. Furthermore, the sensitivity of PCR was 100% and the specificity was 83.33%. Conclusion. It can be concluded that PCR method could be used as a screening method in identifying TRE with large numbers of repeats. However, PCR in TRE disease with small numbers of expanded repeats needs to be followed by sequencing in order to obtain the exact numbers of repeats. Keywords: Trinucleotide Repeat Expansion, Polymerase Chain Reaction, Sequencing, Isolated Hypospadias

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Investigation of Trinucleotide Repeat Expansion in Familial Breast Cancer

10.21236/ada405233 ◽

2002 ◽

Author(s):

Hilmi Ozcelik

Keyword(s):

Breast Cancer ◽

Familial Breast Cancer ◽

Trinucleotide Repeat ◽

Repeat Expansion ◽

Trinucleotide Repeat Expansion

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A Genome-wide Breast Cancer Scan in African Americans

10.21236/ada513444 ◽

2009 ◽

Author(s):

Christopher A. Haiman

Keyword(s):

Breast Cancer ◽

African Americans ◽

Genome Wide ◽

A Genome

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A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

Nature Genetics ◽

10.1038/ng2075 ◽

2007 ◽

Vol 39 (7) ◽

pp. 870-874 ◽

Cited By ~ 1080

Author(s):

David J Hunter ◽

Peter Kraft ◽

Kevin B Jacobs ◽

David G Cox ◽

Meredith Yeager ◽

...

Keyword(s):

Breast Cancer ◽

Association Study ◽

Genome Wide Association Study ◽

Postmenopausal Breast Cancer ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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BIOM-32. ENDOPLASMIC RETICULUM PROTEIN SSR3 DETERMINES AND PREDICTS RESPONSE TO PACLITAXEL IN BREAST CANCER AND GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.063 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi17-vi18

Author(s):

Crismita Dmello ◽

Aarón Sonabend ◽

Víctor Arrieta ◽

Daniel Zhang ◽

Deepak Kanojia ◽

...

Keyword(s):

Breast Cancer ◽

Endoplasmic Reticulum ◽

Glioma Cells ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Precision Oncology ◽

Patient Response ◽

Knock Out ◽

Genome Wide ◽

A Genome

Abstract Paclitaxel (PTX) is one the most potent and commonly used chemotherapies for breast and pancreatic cancer. Given the potency of this drug for glioblastomas (GBM) several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for this disease. In spite of the efficacy of PTX, individual tumors exhibit variable susceptibility to this drug, with response rate in the range of 30%-60%. To identify predictive biomarkers for response to PTX, we performed a genome-wide CRISPR knock-out screen using human glioma cells. The most enriched genes in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort. This led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with response to PTX in breast cancer cells, glioma cells, in multiple intracranial glioma xenografts and in GBM patient derived explant cultures. Knockout of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. In gliomas, SSR3-mediated susceptibility to PTX relates to modulation of phosphorylation of ER stress sensor IRE1α. Thus, by using genome-wide screen combined with patient response data, we discovered a biomarker that demonstrates causal and correlative relationship with response to PTX in breast cancer and GBM. Prospective validation of this biomarker is warranted for its broad implementation for precision oncology.

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Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome

10.1101/2021.04.23.441217 ◽

2021 ◽

Author(s):

Linda Zhou ◽

Chunmin Ge ◽

Thomas Malachowski ◽

Ji Hun Kim ◽

Keerthivasan Raanin Chandradoss ◽

...

Keyword(s):

Fragile X Syndrome ◽

Short Tandem Repeats ◽

Tandem Repeats ◽

Fragile X ◽

Repeat Expansion ◽

Genome Wide ◽

A Genome ◽

In Trans ◽

Surveillance Mechanism ◽

Short Tandem

AbstractShort tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS.One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

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