• Notch signaling
• anti-VEGF
• basal cell carcinoma
• hedgehog signaling
• homopolymeric region
• immune checkpoint inhibitors
• non-melanoma skin cancer
• proteasome inhibitor
• short tandem repeat
• somatic mutation

• P30ES027792 NIH HHS
• R01CA107431 NIH HHS

• biomarkers
• molecular targeted treatment
• predictive markers
• prognostic marker

• Lynch syndrome
• colorectal cancer cell lines
• mismatch repair (MMR) deficiency
• radiation effects
• radiosensitivity

• Humans
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Pilot Projects
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/drug therapy
• Cell Line
• Radiation Tolerance
• Brain Neoplasms
• Neoplastic Syndromes, Hereditary

• gastrointestinal neoplasms
• guidelines as topic

• Humans
• Quality of Life
• Gastrointestinal Neoplasms/drug therapy
• Immunotherapy
• Societies, Medical

• HLA genotype
• Lynch syndrome
• cancer immunoediting
• immune surveillance
• personalized cancer risk

• artificial intelligence
• metastatic colorectal cancer
• ncRNA
• predictive biomarkers
• prognostic biomarkers

5-Fluorouracil (5-FU) is a common chemotherapy drug for patients with advanced colorectal cancer; however, many patients develop resistance to 5-FU and suffer from treatment failure. Discoidin domain receptor 1 (DDR1) is upregulated in multiple cancers and positively associated with chemoresistance. We explored the effect of DDR1a on the cytotoxicity induced by 5-FU in LoVo cells and the underlying mechanism. Therefore, DDR1a overexpression (DDR1a^high) and knockdown in LoVo cell lines (shDDR1a) were constructed to detect cell viability and cytotoxicity induced by 5-FU. The results showed that cell viability of DDR1a^high cells was higher in comparison with that of the control group. When 5-FU (5 µM) was administered, the percentage of apoptotic cells, cytochrome C release and caspase-3 activity was found to be higher in the shDDR1a group than that in the control group. Both of PI3K and MDM2 proteins level decreased in DDR1a^high and shDDR1a, but the BAX/Bcl-2 level in the shDDR1a group increased compared to that in the control. Therefore, DDR1a might be a potential therapeutic target for 5-FU chemoresistance in colorectal cancer.

• 5-fluorouracil
• Discoidin domain receptor 1a
• colorectal cancer
• cytotoxicity
• proliferation

• Vogelgram
• aneuploidy
• chromosomal instability
• clonal evolution
• colorectal cancer
• copy number aberrations
• microsatellite instability
• oncogenetic tree model

• MMR
• Mismatch repair
• Modifier
• NF1
• Neurofibroma
• Neurofibromatosis type 1

• DNA Mismatch Repair/genetics
• Genes, Neurofibromatosis 1
• Humans
• Neurofibroma/genetics
• Neurofibroma/pathology
• Neurofibromatosis 1/genetics

• Universitätsklinikum Halle (Saale) (8960)

• Cancer genomics
• Colorectal cancer
• DNA repair
• Microbiota
• Mutational signatures
• Somatic mutations

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

• 5-hydroxymethylcytosine
• CXCR4 gene expression
• DNA methylation
• colorectal cancer
• epigenetic regulation

• 1R01CA240710 NCI NIH HHS
• 1RO3CA216160-01 NCI NIH HHS
• R01 CA240710 NCI NIH HHS
• U01 CA217078 NCI NIH HHS

• Chromosomal instability
• Colorectal cancer cells
• CpG island methylator phenotype
• DNA profiling
• Microsatellite instability
• Molecular subtype
• Signaling pathways

• Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• DNA, Neoplasm/genetics
• Germ-Line Mutation
• Heterozygote
• Humans
• Microsatellite Repeats/genetics
• Mutation

Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response. This sensitivity is due to a synthetic lethal interaction between FEN1 and MRE11A, which is often mutated in MSI cancers through instabilities at a poly(T) microsatellite repeat. Disruption of ATM is similarly synthetic lethal with FEN1 inhibition, suggesting that disruption of FEN1 function leads to the accumulation of DNA double-strand breaks. These are likely a result of the accumulation of aberrant replication forks, that accumulate as a consequence of a failure in Okazaki fragment maturation, as inhibition of FEN1 is toxic in cells disrupted for the Fanconi anemia pathway and post-replication repair. Furthermore, RAD51 foci accumulate as a consequence of FEN1 inhibition and the toxicity of FEN1 inhibitors increases in cells disrupted for the homologous recombination pathway, suggesting a role for homologous recombination in the resolution of damage induced by FEN1 inhibition. Finally, FEN1 appears to be required for the repair of damage induced by olaparib and cisplatin within the Fanconi anemia pathway, and may play a role in the repair of damage associated with its own disruption.

• Cell Line, Tumor
• Cell Survival/drug effects
• Cisplatin/toxicity
• DNA/drug effects
• DNA/metabolism
• DNA Breaks, Double-Stranded/drug effects
• DNA Damage/drug effects
• DNA Repair/drug effects
• DNA Replication/drug effects
• DNA-Binding Proteins/antagonists & inhibitors
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Down-Regulation/drug effects
• Flap Endonucleases/antagonists & inhibitors
• Flap Endonucleases/genetics
• Flap Endonucleases/metabolism
• Humans
• Hydroxyurea/chemistry
• Hydroxyurea/toxicity
• MRE11 Homologue Protein
• Microsatellite Instability/drug effects
• Mutation
• Phthalazines/toxicity
• Piperazines/toxicity
• Poly(ADP-ribose) Polymerase Inhibitors/toxicity
• RNA Interference
• RNA, Small Interfering/metabolism
• Rad51 Recombinase/genetics

• Cancer Research UK

• Cancer
• DNA damage response
• DNA repair
• Fanconi anemia
• Genomic instability
• RUNX

• cancer
• cancer biology
• mutagenesis in vitro
• p53
• tumor suppressor gene

• biomarker
• colorectal neoplasm
• metastasis
• miRNA
• target gene

• Animals
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics

• Chromosomal instability
• CpG island methylator phenotype
• Metachronous colorectal cancer
• Microsatellite instabillity
• Multiple primary colorectal cancer
• Synchronous colorectal cancer

• Microsatellite instability
• T1
• early colorectal cancer
• lymph node metastasis
• prognosis

• Adult
• Aged
• Aged, 80 and over
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Female
• Humans
• Lymph Nodes/pathology
• Lymphatic Metastasis/pathology
• Male
• Microsatellite Instability
• Microsatellite Repeats/genetics
• Middle Aged
• Neoplasm Staging
• Risk Factors
• Survival Analysis

Stem cell divisions are either asymmetric—in which one daughter cell remains a stem cell and one does not—or symmetric, in which both daughter cells adopt the same fate, either stem or non-stem. Recent studies show that in many tissues operating under homeostatic conditions stem cell division patterns are strongly biased toward the symmetric outcome, raising the question of whether symmetry confers some benefit. Here, we show that symmetry, via extinction of damaged stem-cell clones, reduces the lifetime risk of accumulating phenotypically silent heritable damage (mutations or aberrant epigenetic changes) in individual stem cells. This effect is greatest in rapidly cycling tissues subject to accelerating rates of damage accumulation over time, a scenario that describes the progression of many cancers. A decrease in the rate of cellular damage accumulation may be an important factor favoring symmetric patterns of stem cell division.

Recently, highly symmetric patterns of stem cell division have been observed in a variety of adult mammalian somatic tissues. Here we identify conditions under which this behavior serves as a strategy to protect the organism against mutation accumulation. First, we find that a sufficient number of lifetime stem cell divisions must occur, potentially explaining why stem cell pools with the most symmetric divisions are rapidly cycling. Second, we find that late-occurring mutations must occur rapidly, a scenario known in cancer biology as genetic instability. These findings provide a potential explanation for the observation that cancer risks among large, long-lived organisms fail to rise as expected with lifespan and body size.

• Animals
• Cell Division/genetics
• Genes, APC
• Genomic Instability
• Intestine, Small/cytology
• Mice
• Models, Genetic
• Mutation/genetics
• Stem Cells

• P50 GM076516 NIGMS NIH HHS
• RC2 CA148493 NCI NIH HHS
• RC2-CA148493 NCI NIH HHS
• P50-GM07656 NIGMS NIH HHS

• colorectal cancer
• genetics
• susceptibility

• 15116 Cancer Research UK

Cell lines are invaluable biomedical research tools, and recent literature has emphasized the importance of genotype authentication and characterization. In the present study, 24 out of 27 cell line identities were confirmed by short tandem repeat profiling. The molecular phenotypes of the 24 colon cancer cell lines were examined, and microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) were determined, using the Bethesda panel mononucleotide repeat loci and two epimarker panels, respectively. Furthermore, the BRAF, KRAS and PIK3CA oncogenes were analyzed for mutations in known hotspots, while the entire coding sequences of the PTEN and TP53 tumor suppressors were investigated. Nine cell lines showed MSI. Thirteen and nine cell lines were found to be CIMP positive, using the Issa panel and the Weisenberger et al. panel, respectively. The latter was found to be superior for CIMP classification of colon cancer cell lines. Seventeen cell lines harbored disrupting TP53 mutations. Altogether, 20/24 cell lines had the mitogen-activated protein kinase pathway activating mutually exclusive KRAS or BRAF mutations. PIK3CA and PTEN mutations leading to hyperactivation of the phosphoinositide 3-kinase/AKT pathway were observed in 13/24 cell lines. Interestingly, in four cell lines there were no mutations in neither BRAF, KRAS, PIK3CA nor in PTEN. In conclusion, this study presents molecular features of a large number of colon cancer cell lines to aid the selection of suitable in vitro models for descriptive and functional research.

• Adenocarcinoma/genetics
• Adenocarcinoma/surgery
• Asian People/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/surgery
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Humans
• Microsatellite Instability
• Republic of Korea

• Adenomatous Polyposis Coli Protein/genetics
• Aged
• Alcohol Drinking/adverse effects
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/physiopathology
• Diet
• Diet Records
• Europe
• Female
• Humans
• Life Style
• Logistic Models
• Male
• Meat/adverse effects
• Methylation
• Microsatellite Instability
• Middle Aged
• Mutation/genetics
• Promoter Regions, Genetic/physiology
• Prospective Studies
• Retrospective Studies
• Smoking/adverse effects

• 11388 Cancer Research UK
• G0401527 Medical Research Council
• G1000143 Medical Research Council

Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.

• Anticipation
• MMR genes
• lynch syndrome
• microsatellite instability
• telomere dynamics.
• telomere length

AIM: To investigate endoscopic and clinicopathologic characteristics of early gastric cancer (EGC) according to microsatellite instability phenotype.

METHODS: Data were retrospectively collected from a single tertiary referral center. Of 981 EGC patients surgically treated between December 2003 and October 2007, 73 consecutive EGC patients with two or more microsatellite instability (MSI) mutation [high MSI (MSI-H)] and 146 consecutive EGC patients with one or no MSI mutation (non-MSI-H) were selected. The endoscopic and clinicopathologic features were compared between the MSI-H and non-MSI-H EGC groups.

RESULTS: In terms of endoscopic characteristics, MSI-H EGCs more frequently presented with elevated pattern (OR 4.38, 95% CI: 2.40-8.01, P < 0.001), moderate-to-severe atrophy in the surrounding mucosa (OR 1.91, 95% CI: 1.05-3.47, P = 0.033), antral location (OR 3.99, 95% CI: 2.12-7.52, P < 0.001) and synchronous lesions, compared to non-MSI-H EGCs (OR 2.65, 95% CI: 1.16-6.07, P = 0.021). Other significant clinicopathologic characteristics of MSI-H EGC included predominance of female sex (OR 2.77, 95% CI: 1.53-4.99, P < 0.001), older age (> 70 years) (OR 3.30, 95% CI: 1.57-6.92, P = 0.002), better histologic differentiation (OR 2.35, 95% CI: 1.27-4.34, P = 0.007), intestinal type by Lauren classification (OR 2.34, 95% CI: 1.15-4.76, P = 0.019), absence of a signet ring cell component (OR 2.44, 95% CI: 1.02-5.86, P = 0.046), presence of mucinous component (OR 5.06, 95% CI: 1.27-20.17, P = 0.022), moderate-to-severe lymphoid stromal reaction (OR 3.95, 95% CI: 1.59-9.80, P = 0.003), and co-existing underlying adenoma (OR 2.66, 95% CI: 1.43-4.95, P = 0.002).

CONCLUSION: MSI-H EGC is associated with unique endoscopic and clinicopathologic characteristics including frequent presentation in protruded type, co-existing underlying adenoma, and synchronous lesions.

• Microsatellite instability
• Early gastric cancer
• Endoscopic characteristic
• Advanced gastric cancer

• microsatellite stable
• microsatellite unstable
• colon cancer
• solexa
• gene expression
• ultra-high throughput sequencing
• dna repair genes
• dna damage genes
• 5-fluorouracil

• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/genetics
• DNA Damage
• DNA Repair/genetics
• Drug Resistance, Neoplasm
• Fluorouracil/metabolism
• Fluorouracil/pharmacology
• Gene Expression Profiling
• Genotype
• HCT116 Cells
• HT29 Cells
• High-Throughput Screening Assays
• Humans
• Microsatellite Instability

• R01 CA090559 NCI NIH HHS
• R01 CA090559-07S1 NCI NIH HHS
• CA090559 NCI NIH HHS

Lynch syndrome (LS) is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC) and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

• Adaptor Proteins, Signal Transducing/genetics
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• DNA-Binding Proteins/metabolism
• Female
• Humans
• Lymphatic Metastasis
• Male
• Microsatellite Instability
• Middle Aged
• MutL Protein Homolog 1
• MutS Homolog 3 Protein
• Mutation
• Neoplasm Invasiveness
• Nuclear Proteins/genetics
• Prognosis
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins p21(ras)
• Signal Transduction/genetics
• ras Proteins/genetics

• predictive and prognostic factors
• colorectal cancer
• personalized medicine
• apc
• msi
• mmr
• kras
• braf
• 18qloh
• cimp
• tgf-β
• cin
• mgmt
• tp53
• fobt
• vimentin
• circulating tumor cells

• chemotherapy
• colorectal cancer
• microsatellite instability

• Adenocarcinoma/genetics
• Adenocarcinoma/immunology
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Animals
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/immunology
• Colorectal Neoplasms, Hereditary Nonpolyposis/mortality
• Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
• Female
• Humans
• Male
• Mice
• Microsatellite Instability
• Microsatellite Repeats/genetics
• Survival Rate

• U01 CA086389 NCI NIH HHS
• 1U01 CA 86389 NCI NIH HHS

L1s are one of the most successful autonomous mobile elements in primate genomes. These elements comprise as much as 17% of primate genomes with the majority of insertions occurring via target primed reverse transcription (TPRT). Twin priming, a variant of TPRT, can result in unusual DNA sequence architecture. These insertions appear to be inverted, truncated L1s flanked by target site duplications.

We report on loci with sequence architecture consistent with variants of the twin priming mechanism and introduce dual priming, a mechanism that could generate similar sequence characteristics. These insertions take the form of truncated L1s with hallmarks of classical TPRT insertions but having a poly(T) simple repeat at the 5' end of the insertion. We identified loci using computational analyses of the human, chimpanzee, orangutan, rhesus macaque and marmoset genomes. Insertion site characteristics for all putative loci were experimentally verified.

The 39 loci that passed our computational and experimental screens probably represent inversion-deletion events which resulted in a 5' inverted poly(A) tail. Based on our observations of these loci and their local sequence properties, we conclude that they most probably represent twin priming events with unusually short non-inverted portions. We postulate that dual priming could, theoretically, produce the same patterns. The resulting homopolymeric stretches associated with these insertion events may promote genomic instability and create potential target sites for future retrotransposition events.