| 1. |
- Liu, Wen, et al.
(författare)
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Colorectal cancer risk susceptibility loci in a Swedish population
- 2022
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 61:3, s. 288-300
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Tidskriftsartikel (refereegranskat)abstract
- To search for colorectal cancer (CRC) risk loci, Swedish samples were used for a genome-wide haplotype analysis. A logistic regression model was employed in 2663 CRC cases and 1642 controls in the discovery analysis. Three analyses were done, on all, familial-, and nonfamilial CRC samples and only results with odds ratio (OR) > 1 were analyzed. single nucleotide polymorphism (SNP) analysis did not generate any statistically significant results. Haplotype analysis suggested novel loci, on chromosome 2q36.1 (OR = 1.71, p value = 5.6924 × 10-8 ) in all CRC samples, chromosome 1q43 (OR = 4.04 p value = 3.24 × 10-8 ) in familial CRC samples, and two hits in nonfamilial CRC samples, chromosomes 2q36.1 (OR = 1.71 p value = 5.69 × 10-8 ) and 3p24.3 (OR = 1.62 p value = 6.21 × 10-9 ). Moreover, one locus on chromosome 20q13.33 was suggested in analyses of all samples, and five more novel loci were suggested on chromosomes 10q25.3, 15q,22.31, 17p11.2, 1p34.2, and 3q24. The haplotypes from the analysis of all samples were replicated in a second study of CRC cases and controls from the same part of Sweden. In summary, using haplotype analysis in Swedish CRC samples, the best hits were novel loci and the locus on chromosomes 2q36.1 and 20q13.33 suggested in the analysis of all samples were confirmed in a second cohort. The ORs were often higher than ORs from published genome-wide association study (GWAS). The study suggested it was possible that a risk locus could involve more than one gene, and that haplotypes could give information on the gene or genes possibly involved in the risk at specific locus.
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| 2. |
- Nathan, CA, et al.
(författare)
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TP53 mutations in head and neck cancer
- 2022
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Ingår i: Molecular carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 61:4, s. 385-391
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Sundquist, Kristina, et al.
(författare)
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Diagnostic potential of circulating cell-free nuclear and mitochondrial DNA for several cancer types and nonmalignant diseases : A study on suspected cancer patients
- 2020
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 59:12, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- Circulating cell-free nuclear DNA (nDNA) has been implicated in individual cancer types with a diagnostic value; however, the role of cell-free mitochondrial DNA (mtDNA) in cancers is controversial. We aimed to investigate and compare the diagnostic potential of both nDNA and mtDNA for multiple cancers and to investigate their ability to distinguish multiple cancers from healthy controls and from nonmalignant diseases. We also investigated the prognostic value of both nDNA and mtDNA. The absolute copy number of circulating DNAs in suspected cancer patients (n = 286) referred to a cancer diagnostic center and healthy controls (n = 109) was quantified by droplet digital polymerase chain reaction. Among the suspected cancer patients, 66 (23%) were diagnosed with various cancers, 193 (67%) with nonmalignant diseases, and 27 (10%) with no active disease. Levels of nDNA were significantly higher in cancers (copies/μl; mean ± SD, 21.0 ± 14.2) as compared with nonmalignant diseases (15.2 ± 10.0) and controls (9.3 ± 4.1). In contrast, levels of mtDNA were significantly lower in cancers (copies/μl; mean ± SD, 68,557 ± 66,663) and nonmalignant diseases (60,174 ± 55,831) as compared with controls (98,714 ± 77,789). Receiver operating curve analysis showed that nDNA not only could distinguish multiple cancers from controls (area under curve [AUC] = 0.78; 95% confidence interval [CI] = 0.70-0.86) but also from nonmalignant diseases (AUC = 0.68; 95% CI = 0.59-0.76). However, mtDNA could only differentiate cancers from controls (AUC = 0.65; 95% CI = 0.56-0.73). Higher levels of nDNA were also associated with increased mortality in the cancer patients (hazard ratio = 2.3; 95% CI = 1.1-4.7). Circulating cell-free nDNA, but not the mtDNA, could distinguish multiple cancers from nonmalignant diseases and was associated with poor survival of cancer patients.
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| 4. |
- Liu, Anbu, et al.
(författare)
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DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
- 2024
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Ingår i: Molecular Carcinogenesis. - 0899-1987. ; 63:1, s. 75-93
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild-type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first-line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild-type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT-targeted therapy. The development of drug-resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
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