| 321. |
- Tannous, Bakhos A., et al.
(författare)
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Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 105:17, s. 1322-1331
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Tidskriftsartikel (refereegranskat)abstract
- Background Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.Methods We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.Results Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.Conclusions Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.
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| 322. |
- Terry, Paul, et al.
(författare)
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Fruit, vegetables, dietary fiber, and risk of colorectal cancer
- 2001
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 93:7, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several recent large prospective cohort studies have failed to demonstrate the presumed protective effect of fruit, vegetable, and dietary fiber consumption on colorectal cancer risk. To further explore this issue, we have examined these associations in a population that consumes relatively low amounts of fruit and vegetables and high amounts of cereals. METHODS: We examined data obtained from a food-frequency questionnaire used in a population-based prospective mammography screening study of women in central Sweden. Women with colorectal cancer diagnosed through December 31, 1998, were identified by linkage to regional cancer registries. Cox proportional hazards models were used to estimate relative risks. All statistical tests were two-sided. RESULTS: During an average 9.6 years of follow-up of 61 463 women, we observed 460 incident cases of colorectal cancer (291 colon cancers, 159 rectal cancers, and 10 cancers at both sites). In the entire study population, total fruit and vegetable consumption was inversely associated with colorectal cancer risk. Subanalyses showed that this association was due largely to fruit consumption. The association was stronger, however, and the dose-response effect was more evident among individuals who consumed the lowest amounts of fruit and vegetables. Individuals who consumed less than 1.5 servings of fruit and vegetables per day had a relative risk for developing colorectal cancer of 1.65 (95% confidence interval = 1.23 to 2.20; P(trend) =.001) compared with individuals who consumed more than 2.5 servings. We observed no association between colorectal cancer risk and the consumption of cereal fiber, even at amounts substantially greater than previously examined, or of non-cereal fiber. CONCLUSIONS: Individuals who consume very low amounts of fruit and vegetables have the greatest risk of colorectal cancer. Relatively high consumption of cereal fiber does not appear to lower the risk of colorectal cancer.
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| 323. |
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| 324. |
- Thompson, D, et al.
(författare)
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Cancer Incidence in BRCA1 mutation carriers
- 2002
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 94:18, s. 1358-1365
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Tidskriftsartikel (refereegranskat)abstract
- Background: Germline BRCA1 mutations confer a substantial lifetime risk of breast and ovarian cancer, but whether cancer at other sites is increased is less clear. To evaluate the risks of other cancers in BRCA1 mutation carriers, we conducted a cohort study of 11 847 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America. Methods: The observed cancer incidence was compared with the expected cancer incidence based on population cancer rates. Relative risks (RRs) of each cancer type in BRCA1 carriers relative to risks for the general population were estimated by weighting individuals according to their estimated probability of being a mutation carrier. All statistical tests were two-sided. Results: BRCA1 mutation carriers were at a statistically significantly increased risk for several cancers, including pancreatic cancer (RR = 2.26, 95% confidence interval [CI] = 1.26 to 4.06, P = .004) and cancer of the uterine body and cervix (uterine body RR = 2.65, 95% CI = 1.69 to 4.16, P<.001; cervix RR = 3.72, 95% CI = 2.26 to 6.10, P<.001). There was some evidence of an elevated risk of prostate cancer in mutation carriers younger than 65 years old (RR = 1.82, 95% CI = 1.01 to 3.29, P = .05) but not in those 65 years old or older (RR = 0.84, 95% CI = 0.53 to 1.33, P = .45). Overall, increases in the risk for cancer at sites other than the breast or ovary were small and evident in women (RR = 2.30, 95% CI = 1.93 to 2.75, P = .001) but not in men (RR = 0.95, 95% CI = 0.81 to 1.12, P = .58). Conclusions: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men. BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women.
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| 325. |
- Thrift, Aaron P, et al.
(författare)
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Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus : a Mendelian randomization study.
- 2014
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding.METHODS: We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
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| 326. |
- Tian, Yu, et al.
(författare)
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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:8, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
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| 327. |
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| 328. |
- Trabert, Britton, et al.
(författare)
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Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 111:2, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations.Methods: Studies included: 1) a case-control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case-control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression.Results: In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk.Conclusions: In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.
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| 329. |
- Travis, L. B., et al.
(författare)
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Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin´s lymphoma
- 1995
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 87:7, s. 524-530
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Cyclophosphamide is an established bladder carcinogen, but few studies have examined the relationship between dose and effect. The largest analysis to date included only seven cases of bladder cancer. No investigation has estimated the risk of kidney cancer. PURPOSE: The purpose of this study was to quantify the risk of bladder and kidney cancer following cyclophosphamide therapy. METHODS: Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy. Detailed information on chemotherapeutic drugs and cumulative dose received was collected for all subjects. Radiation dose to the target organ was estimated from individual radiotherapy records. Evaluations of the risk of second cancer as a result of treatment with cyclophosphamide alone, radiation alone, or both therapies were made relative to those patients who were exposed to neither treatment modality. RESULTS: A significant 4.5-fold risk of bladder cancer (95% confidence interval [CI] = 1.5-13.6) followed therapy with cyclophosphamide, and risk was dependent upon cumulative dose. Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold (95% CI = 1.3-29) and 14.5-fold (95% CI = 2.3-94) risks of bladder malignancy followed cumulative doses of 20-49 g and 50 g or more, respectively (P value for trend = .004). Radiotherapy given without cyclophosphamide was associated with a nonsignificant increased risk of bladder malignancy. Excess bladder cancer risk following treatment with both radiotherapy and cyclophosphamide was as expected if individual risks were summed. Neither radiotherapy nor cyclophosphamide was associated with excesses of kidney cancer. CONCLUSIONS: Cyclophosphamide-related bladder cancer is dose dependent. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up. At cumulative doses of 50 g or more, the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients. IMPLICATIONS: The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points. The risk of secondary bladder malignancy and other late sequelae of therapy must be carefully weighted against the curative gains provided by cyclophosphamide. Moreover, long-term side effects of therapy that might be acceptable in cancer treatment may need to be re-evaluated for patients with non-neoplastic disorders.
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| 330. |
- Travis, Lois B., et al.
(författare)
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Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma
- 2005
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 97:19, s. 1428-37
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death. METHODS: Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20- < 40 Gy, or > or = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors. RESULTS: Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents. CONCLUSIONS: Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.
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