scholarly journals Mismatch-repair signature mutations activate gene enhancers across colorectal cancer epigenomes

2018 ◽  
Author(s):  
Stevephen Hung ◽  
Alina Saiakhova ◽  
Zachary Faber ◽  
Cynthia F. Bartels ◽  
Devin Neu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Selective Advantage ◽  
Regulatory Elements ◽  
Enhancer Activity ◽  
Activating Mutations ◽  
Show Evidence ◽  
Metastasis Model ◽  
Indel Rate ◽  
Activate Gene

AbstractCommonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate or augment enhancers in CRC tumor epigenomes to provide a selective advantage.

scholarly journals Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Stevephen Hung ◽  
Alina Saiakhova ◽  
Zachary J Faber ◽  
Cynthia F Bartels ◽  
Devin Neu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Selective Advantage ◽  
Regulatory Elements ◽  
Enhancer Activity ◽  
Activating Mutations ◽  
Show Evidence ◽  
Metastasis Model ◽  
In Cis ◽  
Activate Gene

Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate enhancers in CRC tumor epigenomes to provide a selective advantage.

scholarly journals Author response: Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes

2018 ◽  
Author(s):  
Stevephen Hung ◽  
Alina Saiakhova ◽  
Zachary J Faber ◽  
Cynthia F Bartels ◽  
Devin Neu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Author Response ◽  
Human Colorectal Cancer ◽  
Activate Gene

scholarly journals Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5434
Author(s):  
Emre Küçükköse ◽  
G. Emerens Wensink ◽  
Celine M. Roelse ◽  
Susanne J. van Schelven ◽  
Daniëlle A. E. Raats ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Mismatch Repair ◽  
Therapy Response ◽  
Treatment Resistance ◽  
Poor Response ◽  
Dna Mismatch ◽  
Activating Mutations ◽  
Future Drug ◽  
Mismatch Repair Status

DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.

scholarly journals Redundant and non-redundant cytokine-activated enhancers control Csn1s2b expression in the lactating mouse mammary gland

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hye Kyung Lee ◽  
Michaela Willi ◽  
Tyler Kuhns ◽  
Chengyu Liu ◽  
Lothar Hennighausen
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Mammary Gland ◽  
Regulatory Elements ◽  
Mouse Mammary Gland ◽  
Mouse Genetics ◽  
Distal Enhancer ◽  
Enhancer Activity ◽  
Super Enhancer ◽  
Activate Gene

AbstractEnhancers are transcription factor platforms that synergize with promoters to control gene expression. Here, we investigate enhancers that activate gene expression several hundred-fold exclusively in the lactating mouse mammary gland. Using ChIP-seq for activating histone marks and transcription factors, we identify two candidate enhancers and one super-enhancer in the Csn1s2b locus. Through experimental mouse genetics, we dissect the lactation-specific distal enhancer bound by the mammary-enriched transcription factors STAT5 and NFIB and the glucocorticoid receptor. While deletions of canonical binding motifs for NFIB and STAT5, individually or combined, have a limited biological impact, a non-canonical STAT5 site is essential for enhancer activity during lactation. In contrast, the intronic enhancer contributes to gene expression only in late pregnancy and early lactation, possibly by interacting with the distal enhancer. A downstream super-enhancer, which physically interacts with the distal enhancer, is required for the functional establishment of the Csn1s2b promoter and gene activation. Lastly, NFIB binding in the promoter region fine-tunes Csn1s2b expression. Our study provides comprehensive insight into the anatomy and biology of regulatory elements that employ the JAK/STAT signaling pathway and preferentially activate gene expression during lactation.

Slip Slidin' Away: A Duodecen-nial Review of Targeted Genes in Mismatch Repair Deficient Colorectal Cancer

2007 ◽  
Vol 13 (3) ◽  
pp. 229-257 ◽  
Author(s):  
Ellen C. Royrvik ◽  
Terje Ahlquist ◽  
Torbjorn Rognes ◽  
Ragnhild A. Lothe
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair

scholarly journals Sequence Variation and Haplotype Structure at the HumanHFELocus

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1609-1623 ◽  
Author(s):  
Christopher Toomajian ◽  
Martin Kreitman
Keyword(s):  
High Frequency ◽  
Nucleotide Diversity ◽  
Sequence Variation ◽  
Hla Class I ◽  
Selective Advantage ◽  
European Ancestry ◽  
Iron Regulation ◽  
Intragenic Recombination ◽  
Nucleotide Variability ◽  
Show Evidence

AbstractThe HFE locus encodes an HLA class-I-type protein important in iron regulation and segregates replacement mutations that give rise to the most common form of genetic hemochromatosis. The high frequency of one disease-associated mutation, C282Y, and the nature of this disease have led some to suggest a selective advantage for this mutation. To investigate the context in which this mutation arose and gain a better understanding of HFE genetic variation, we surveyed nucleotide variability in 11.2 kb encompassing the HFE locus and experimentally determined haplotypes. We fully resequenced 60 chromosomes of African, Asian, or European ancestry as well as one chimpanzee, revealing 41 variable sites and a nucleotide diversity of 0.08%. This indicates that linkage to the HLA region has not substantially increased the level of HFE variation. Although several haplotypes are shared between populations, one haplotype predominates in Asia but is nearly absent elsewhere, causing higher than average genetic differentiation among the three major populations. Our samples show evidence of intragenic recombination, so the scarcity of recombination events within the C282Y allele class is consistent with selection increasing the frequency of a young allele. Otherwise, the pattern of variability in this region does not clearly indicate the action of positive selection at this or linked loci.

scholarly journals Compliance with mismatch repair testing in pT1 colorectal cancer diagnosed before the age of 70 years

2021 ◽  
Author(s):  
Berbel L. M. Ykema ◽  
◽  
Iris D. Nagtegaal ◽  
Koert Kuhlmann ◽  
Annemarie M. van Berkel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair
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