Folic acid enforces DNA methylation-mediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer

AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

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Synthetic lethality: the road to novel therapies for breast cancer

Endocrine Related Cancer ◽

10.1530/erc-16-0228 ◽

2016 ◽

Vol 23 (10) ◽

pp. T39-T55 ◽

Cited By ~ 10

Author(s):

Kiranjit K Dhillon ◽

Ilirjana Bajrami ◽

Toshiyasu Taniguchi ◽

Christopher J Lord

Keyword(s):

Breast Cancer ◽

Synthetic Lethality ◽

Tumour Suppressor ◽

Tumour Suppressor Genes ◽

Novel Therapies ◽

Loss Of Function ◽

Molecular Processes ◽

Suppressor Genes ◽

The Road ◽

Over Time

When theBRCA1andBRCA2tumour suppressor genes were identified in the early 1990s, the immediate implications of mapping, cloning and delineating the sequence of these genes were that individuals in families with aBRCAgene mutation could be tested for the presence of a mutation and their risk of developing cancer could be predicted. Over time though, the discovery ofBRCA1andBRCA2has had a much greater influence than many might have imagined. In this review, we discuss how the discovery ofBRCA1andBRCA2has not only provided an understanding of the molecular processes that drive tumourigenesis but also reignited an interest in therapeutically exploiting loss-of-function alterations in tumour suppressor genes.

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Is DNA methylation of tumour suppressor genes epigenetic?

eLife ◽

10.7554/elife.02475 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 14

Author(s):

Kevin Struhl

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Cancer Cells ◽

Tumour Suppressor ◽

Tumour Suppressor Genes ◽

Suppressor Genes ◽

Colorectal Cancer Cells ◽

Transcriptional Pathway

In colorectal cancer cells, a non-epigenetic transcriptional pathway that is mediated by an oncogene maintains DNA methylation of tumour suppressor genes

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CRISPR–Cas9/long-read sequencing approach to identify cryptic mutations in BRCA1 and other tumour suppressor genes

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107320 ◽

2020 ◽

pp. jmedgenet-2020-107320 ◽

Cited By ~ 1

Author(s):

Tom Walsh ◽

Silvia Casadei ◽

Katherine M Munson ◽

Mary Eng ◽

Jessica B Mandell ◽

...

Keyword(s):

Breast Cancer ◽

Bilateral Breast Cancer ◽

Tumour Suppressor ◽

Tumour Suppressor Genes ◽

Single Nucleotide Variants ◽

Suppressor Genes ◽

Small Indels ◽

Long Reads ◽

Long Read ◽

Genomic Regions

AbstractCurrent clinical approaches for mutation discovery are based on short sequence reads (100–300 bp) of exons and flanking splice sites targeted by multigene panels or whole exomes. Short-read sequencing is highly accurate for detection of single nucleotide variants, small indels and simple copy number differences but is of limited use for identifying complex insertions and deletions and other structural rearrangements. We used CRISPR-Cas9 to excise complete BRCA1 and BRCA2 genomic regions from lymphoblast cells of patients with breast cancer, then sequenced these regions with long reads (>10 000 bp) to fully characterise all non-coding regions for structural variation. In a family severely affected with early-onset bilateral breast cancer and with negative (normal) results by gene panel and exome sequencing, we identified an intronic SINE-VNTR-Alu retrotransposon insertion that led to the creation of a pseudoexon in the BRCA1 message and introduced a premature truncation. This combination of CRISPR–Cas9 excision and long-read sequencing reveals a class of complex, damaging and otherwise cryptic mutations that may be particularly frequent in tumour suppressor genes replete with intronic repeats.

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