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Clendenen, T. V., Ge, W., Koenig, K. L., Afanasyeva, Y., Agnoli, C., Brinton, L. A., . . . Liu, M. (2019). Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model. Breast Cancer Research, 21, Article ID 42.
Open this publication in new window or tab >>Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model
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2019 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 21, article id 42Article in journal (Refereed) Published
Abstract [en]

Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Mullerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.

Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.

Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.

Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Breast cancer risk prediction, Anti-Mullerian hormone, Testosterone, Gail model
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157955 (URN)10.1186/s13058-019-1126-z (DOI)000462251300001 ()30890167 (PubMedID)
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-05-08Bibliographically approved
Zamaratskaia, G., Mhd Omar, N. A., Brunius, C., Hallmans, G., Johansson, J.-E., Andersson, S.-O., . . . Landberg, R. (2019). Consumption of whole grain/bran rye instead of refined wheat decrease concentrations of TNF-R2, e-selectin, and endostatin in an exploratory study in men with prostate cancer. Clinical Nutrition, Article ID S0261-5614(19)30009-3.
Open this publication in new window or tab >>Consumption of whole grain/bran rye instead of refined wheat decrease concentrations of TNF-R2, e-selectin, and endostatin in an exploratory study in men with prostate cancer
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2019 (English)In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, article id S0261-5614(19)30009-3Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND & AIMS: Rye consumption has shown beneficial effects on prostate cancer tumors, as indicated by slower initial tumor growth in animal models and lowering of prostate-specific antigen (PSA) in humans. This study evaluated the effects of whole grain/bran rye consumption on low-grade inflammation and endothelial function biomarkers in men with prostate cancer.

METHODS: Seventeen men with untreated, low-grade prostate cancer consumed 485 g rye whole grain and bran products (RP) per day or refined wheat products with added cellulose (WP) in a randomized crossover design. Fasting blood samples were taken before and after 2, 4, and 6 weeks of treatment.

RESULTS: Concentrations of tumor nuclear factor-receptor 2 (TNF-R2), e-selectin, and endostatin were significantly lower after consumption of the RP diet compared with WP (p < 0.05). Cathepsin S concentration was positively correlated to TNF-R2 and endostatin concentrations across all occasions. Strong correlations were consistently found between intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and between interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA). No effect of intervention was found in 92 inflammation-related protein biomarkers measured in a proximity extension assay.

CONCLUSIONS: RP diet lowered TNF-R2, e-selectin, and endostatin, compared with WP in men with prostate cancer. These effects were accompanied by a reduction in PSA.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Endothelial function markers, Low-grade inflammatory markers, Plasma, Prostate cancer, Refined wheat, Whole grain/bran rye
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-156369 (URN)10.1016/j.clnu.2019.01.007 (DOI)30685298 (PubMedID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-27
Thomsen, H., Chattopadhyay, S., Weinhold, N., Vodicka, P., Vodickova, L., Hoffmann, P., . . . Försti, A. (2019). Genome-wide association study of monoclonal gammopathy of unknown significance (MGUS): comparison with multiple myeloma [Letter to the editor]. Leukemia, 33(7), 1817-1821
Open this publication in new window or tab >>Genome-wide association study of monoclonal gammopathy of unknown significance (MGUS): comparison with multiple myeloma
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 7, p. 1817-1821Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-156453 (URN)10.1038/s41375-019-0396-x (DOI)000473724900026 ()30737484 (PubMedID)
Available from: 2019-02-15 Created: 2019-02-15 Last updated: 2019-08-05Bibliographically approved
Santucci-Pereira, J., Zeleniuch-Jacquotte, A., Afanasyeva, Y., Zhong, H., Slifker, M., Peri, S., . . . Russo, J. (2019). Genomic signature of parity in the breast of premenopausal women. Breast Cancer Research, 21(1), Article ID 46.
Open this publication in new window or tab >>Genomic signature of parity in the breast of premenopausal women
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2019 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 21, no 1, article id 46Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women.

METHODS: Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues.

RESULTS: Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues.

CONCLUSIONS: Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

Keywords
Breast cancer risk, Breast differentiation, Gene expression profiling, Immune response, Normal breast transcriptome, Parous and nulliparous breast transcriptome, Pregnancy
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-158788 (URN)10.1186/s13058-019-1128-x (DOI)000463748600001 ()30922380 (PubMedID)2-s2.0-85063811942 (Scopus ID)
Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-16Bibliographically approved
Berggrund, M., Enroth, S., Lundberg, M., Assarsson, E., Stålberg, K., Lindquist, D., . . . Gyllensten, U. (2019). Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay. Molecular & Cellular Proteomics, 18(4), 735-743, Article ID RA118.001208.
Open this publication in new window or tab >>Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743, article id RA118.001208Article in journal (Refereed) Published
Abstract [en]

Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

Keywords
Blood*, Cancer biomarker(s), Cervical cancer, Clinical proteomics, Human Papillomavirus, Personalized medicine, Screening
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-156660 (URN)10.1074/mcp.RA118.001208 (DOI):000466934700009 ()30692274 (PubMedID)
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-06-13Bibliographically approved
Kurbasic, A., Fraser, A., Mogren, I., Hallmans, G., Franks, P. W., Rich-Edwards, J. W. & Timpka, S. (2019). Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study. American Journal of Hypertension, 32(4), 331-334
Open this publication in new window or tab >>Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study
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2019 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 32, no 4, p. 331-334Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown.

METHODS: We studied 13,893 first-born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Västerbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population-based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable poisson and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N = 135).

RESULTS: Offspring participants of women with HDP (N = 383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2-hour 75 g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses.

CONCLUSION: Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
blood pressure, cardiovascular diseases, epidemiologic studies, hypertension, pre-eclampsia, pregnancy, preventive medicine, “Hypertension, Pregnancy-Induced”
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-157849 (URN)10.1093/ajh/hpy176 (DOI)000462548000003 ()30475953 (PubMedID)2-s2.0-85062985965 (Scopus ID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-15Bibliographically approved
Erzurumluoglu, A. M., Liu, M., Jackson, V. E., Barnes, D. R., Datta, G., Melbourne, C. A., . . . Howson, J. M. (2019). Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry
Open this publication in new window or tab >>Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
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2019 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed) Epub ahead of print
Abstract [en]

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-156372 (URN)10.1038/s41380-018-0313-0 (DOI)30617275 (PubMedID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-27
Gylling, B., Myte, R., Ulvik, A., Ueland, P. M., Midttun, Ø., Schneede, J., . . . Palmqvist, R. (2019). One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk. International Journal of Cancer, 144(5), 947-956
Open this publication in new window or tab >>One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 5, p. 68p. 947-956Article in journal (Other academic) Published
Abstract [en]

Background: One-carbon metabolism biomarker are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs.

Objective: We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk.

Design: The relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1211 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5´-phosphate, and riboflavin. Associations with CRC risk were estimated using conditional logistic regression.

Results: The ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. Associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high versus low B-vitamin status).

Conclusions: Ratio-based B-vitamin markers were good predictors of total B-vitamin status, and displayed similar associations with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice to aid interpretation of tHcy results.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. p. 68
Keywords
Biomarkers, colorectal cancer, metabolite ratios, B-vitamins, one-carbon metabolism
National Category
Clinical Laboratory Medicine
Research subject
Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-142854 (URN)10.1002/ijc.31606 (DOI)000455041700003 ()29786139 (PubMedID)
Funder
Swedish Cancer Society, 12/501Swedish Cancer Society, 14/780
Note

Originally included in thesis in manuscript form

Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2019-02-14Bibliographically approved
Ge, W., Clendenen, T. V., Afanasyeva, Y., Koenig, K. L., Agnoli, C., Brinton, L. A., . . . Zeleniuch-Jacquotte, A. (2018). Circulating anti-Müllerian hormone and breast cancer risk: a study in ten prospective cohorts. International Journal of Cancer, 142(11), 2215-2226
Open this publication in new window or tab >>Circulating anti-Müllerian hormone and breast cancer risk: a study in ten prospective cohorts
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2018 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 11, p. 2215-2226Article in journal (Refereed) Published
Abstract [en]

A strong positive association has been observed between circulating anti‐Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case–control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme‐linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (ptrend across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31–1.94). Though the test for interaction was not statistically significant (pinteraction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: ORQ4–Q1 = 1.96, 95% CI = 1.46–2.64, ptrend <0.0001; ER+/PR−: ORQ4–Q1 = 0.82, 95% CI = 0.40–1.68, ptrend = 0.51; ER−/PR+: ORQ4–Q1 = 3.23, 95% CI = 0.48–21.9, ptrend = 0.26; ER−/PR−: ORQ4–Q1 = 1.15, 95% CI = 0.63–2.09, ptrend = 0.60. The association was observed for both pre‐ (ORQ4–Q1= 1.35, 95% CI = 1.05–1.73) and post‐menopausal (ORQ4–Q1 = 1.61, 95% CI = 1.03–2.53) breast cancer (pinteraction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.

What's new? To make informed decisions about screening and prevention, women need tools to accurately assess their breast cancer risk. Young women have few predictive biomarkers to look to; estrogen and progesterone are only weakly predictive before menopause. Anti-Müllerian hormone (AMH), which strongly correlates with age at menopause, may also correlate with breast cancer risk, according to some previous data. Here, the authors test this correlation by conducting nested case-control studies within ten different cohorts. They found that breast cancer risk increased along with increasing AMH concentration, confirming this hormone as a possible biomarker for breast cancer.

Place, publisher, year, edition, pages
Hoboken: John Wiley & Sons, 2018
Keywords
AMH, anti-Müllerian hormone, breast cancer, nested case-control study
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-146526 (URN)10.1002/ijc.31249 (DOI)000429545800003 ()29315564 (PubMedID)
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2019-05-24Bibliographically approved
Li, W., Middha, M., Bicak, M., Sjoberg, D. D., Vertosick, E., Dahlin, A., . . . Klein, R. J. (2018). Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival. European Urology, 74(6), 710-719
Open this publication in new window or tab >>Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival
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2018 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 710-719Article in journal (Refereed) Published
Abstract [en]

Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.

Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.

Design, setting, and participants: Blood samples from 11 506 men in Sweden were collected during 1991–1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped.

Outcome measurements and statistical analysis: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1 × 10−6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis.

Results and limitations: We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p < 5 × 10−8) and replicated in an independent cohort: rs73055188 (p = 5.27 × 10−9, per-allele hazard ratio [HR] = 2.27, 95% confidence interval [CI] 1.72–2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p < 1 × 10−6) and replicated in an independent cohort: rs2702185 (p = 7.1 × 10−7, per-allele HR = 2.55, 95% CI = 1.76–3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups.

Conclusions: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer.

Patient summary: We identify two genetic markers that are associated with prostate-cancer-specific survival time.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
AOX1, Expression quantitative trait locus, Genome-wide association study, Prostate cancer, Survival analysis
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-154930 (URN)10.1016/j.eururo.2018.06.021 (DOI)000450121100014 ()30289108 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/559Swedish Research Council, 2016-02974
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9581-3845

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