| 1. |
- Andersson, Mattias K, 1979, et al.
(författare)
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Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling
- 2017
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Ingår i: Jnci-Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target. Methods: Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided. Results: The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control +/- SD = 27.2 +/- 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control +/- SD = 34.9 +/- 20.3, P = .006; ACCX6, % growth of control +/- SD = 24.1 +/- 17.5, P = .04). Conclusions: MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.
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| 2. |
- Aydin, Denis, et al.
(författare)
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Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study.
- 2011
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 103:16, s. 1264-76
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Tidskriftsartikel (refereegranskat)abstract
- It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents.
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| 3. |
- Borregales, L. D., et al.
(författare)
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Grade Migration of Prostate Cancer in the United States During the Last Decade
- 2022
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Ingår i: Jnci-Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 114:7, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- Background Prostate cancer (PC) screening guidelines have changed over the last decade to reduce overdiagnosis and overtreatment of low-grade disease. We sought to examine and attempt to explain how changes in screening strategies have impacted temporal trends in Gleason grade group (GG) PC at diagnosis and radical prostatectomy pathology. Methods Using the Surveillance, Epidemiology, and End Results Registry database, we identified 438 432 men with newly diagnosed PC during 2010-2018. Temporal trends in incidence of GG at biopsy, radical prostatectomy pathology, prostate-specific antigen (PSA) level, and metastasis at diagnosis were examined. The National Health Interview Survey database was examined to evaluate trends in PSA-screening rates, and a literature review evaluating magnetic resonance imaging and biomarkers utilization during this period was performed. Results Between 2010 and 2018, the incidence of low-grade PC (GG1) decreased from 52 to 26 cases per 100 000 (P < .001). The incidence of GG1 as a proportion of all PC decreased from 47% to 32%, and the proportion of GG1 at radical prostatectomy pathology decreased from 32% to 10% (P < .001). However, metastases at diagnosis increased from 3.0% to 5.2% (P < .001). During 2010-2013, PSA screening rates in men aged 50-74 years declined from 39 to 32 per 100 men and remained stable. Utilization rates of magnetic resonance imaging and biomarkers modestly increased from 7.2% in 2012 to 17% in 2019 and 1.3% in 2012 to 13% in 2019, respectively. Conclusions We found a significant decrease in the diagnosis and treatment of GG1 PC between 2010 and 2018. Changes in PSA screening practices appear as the primary contributor. Public health efforts should be directed toward addressing the increase in the diagnoses of metastatic PC.
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| 4. |
- Borregales, L. D., et al.
(författare)
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Response to Takahashi
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 114:11, s. 1557-1558
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Bouwhuis, Marna G, et al.
(författare)
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Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
- 2009
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 101:12, s. 869-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. METHODS: Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. RESULTS: When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). CONCLUSIONS: In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.
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| 6. |
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| 7. |
- Ek, Weronica E, et al.
(författare)
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Germline genetic contributions to risk for esophageal adenocarcinoma, barrett's esophagus, and gastroesophageal reflux
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:22, s. 1711-1718
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Tidskriftsartikel (refereegranskat)abstract
- Background Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. Methods We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were twosided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10-9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10-7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10-6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. Conclusions We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. © The Author 2013.
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| 8. |
- Eliassen, A Heather, et al.
(författare)
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Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.
- 2012
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 104:24, s. 1905-16
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Tidskriftsartikel (refereegranskat)abstract
- Background Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. Methods We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Results Statistically significant inverse associations with breast cancer were observed for α-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, Ptrend = .04), β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, Ptrend = .02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, Ptrend = .05), lycopene (RR = 0.78, 95% CI = 0.62 to 0.99, Ptrend = .02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, Ptrend = .01). β-Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER(-)) than for ER(+) tumors (eg, β-carotene: ER(-): top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, Ptrend = .001; ER(+): RR = 0.83, 95% CI = 0.66 to 1.04, Ptrend = .06; Pheterogeneity = .01). Conclusions This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer.
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| 9. |
- Grenabo, Anna, et al.
(författare)
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Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam.
- 2007
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 99:17, s. 1296-303
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of prostate cancer has increased substantially since it became common practice to screen asymptomatic men for the disease. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in 1993 to determine how prostate-specific antigen (PSA) screening affects prostate cancer mortality. Variations in the screening algorithm, such as the interval between screening rounds, likely influence the morbidity, mortality, and quality of life of the screened population.We compared the number and characteristics of interval cancers, defined as those diagnosed during the screening interval but not detected by screening, in men in the screening arm of the ERSPC who were aged 55-65 years at the time of the first screening and were participating through two centers of the ERSPC: Gothenburg (2-year screening interval, n = 4202) and Rotterdam (4-year screening interval, n = 13301). All participants who were diagnosed with prostate cancer through December 31, 2005, but at most 10 years after the initial screening were ascertained by linkage with the national cancer registries. A potentially life-threatening (aggressive) interval cancer was defined as one with at least one of the following characteristics at diagnosis: stage M1 or N1, plasma PSA concentration greater than 20.0 ng/mL, or Gleason score greater than 7. We used Mantel Cox regression to assess differences between rates of interval cancers and aggressive interval cancers at the two centers. All statistical tests were two-sided.The 10-year cumulative incidence of all prostate cancers in Rotterdam versus Gothenburg was 1118 (8.41%) versus 552 (13.14%) (P<.001), the cumulative incidence of interval cancer was 57 (0.43%) versus 31 (0.74%) (P = .51), and the cumulative incidence of aggressive interval cancer was 15 (0.11%) versus 5 (0.12%) (P = .72).The rate of interval cancer, especially aggressive interval cancer, was low in this study. The 2-year screening interval had higher detection rates than the 4-year interval but did not lead to lower rates of interval and aggressive interval prostate cancers.
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| 10. |
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