Stig E Bojesen

Publications of Stig E Bojesen

• The role of genetic breast cancer susceptibility variants as prognostic factors.

  Authors: Peter A Fasching, Paul D P Pharoah, Angela Cox, Heli Nevanlinna, Stig E Bojesen, Thomas Karn, Annegien Broeks, Flora E van Leeuwen, Laura J van 't Veer, Renate Udo [......] Sara J Schonfeld, Hoda Anton-Culver, Peter Devilee, Matthias W Beckmann, Dennis J Slamon, Kelly-Anne Phillips, Jonine D Figueroa, Manjeet K Humphreys, Douglas F Easton, Marjanka K Schmidt

  Human molecular genetics. 04/2012;

  BACKGROUNDRecent genome-wide association studies identified eleven single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for theirBACKGROUNDRecent genome-wide association studies identified eleven single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance.METHODSConfirmed BC risk SNPs rs17468277(CASP8), rs1982073(TGFB1), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7), rs6504950(COX11) and rs10941679(5p12) were genotyped for 25,853 BC patients with available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and prognosis in a different patient group.RESULTSOne of the eleven SNPs, rs3803662(TOX3) and none of 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action (hazard ratio (HR) of rare homozygous carriers=1.21; 95%CI: 1.09-1.35, P=0.0002 and HR=1.29; 95%CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively). This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis.CONCLUSIONWith the exception of rs3803662(TOX3), there was no evidence that any of the SNPs associated with breast cancer susceptibility were associated with BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

• 11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer.

  Authors: Diether Lambrechts, Therese Truong, Christina Justenhoven, Manjeet K Humphreys, Jean Wang, John L Hopper, Gillian S Dite, Carmel Apicella, Melissa C Southey, Marjanka K Schmidt [......] Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Annika Lindblom, Sara Margolin, Alison M Dunning, Paul D P Pharoah, Douglas F Easton, Pascal Guénel, Hiltrud Brauch

  Human mutation. 03/2012;

  A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative riskA recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P = 3 × 10-9) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10-39). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.

• CHRNA3 genotype, nicotine dependence, lung function and disease in the general population.

  Authors: Diljit Kaur-Knudsen, Børge G Nordestgaard, Stig E Bojesen

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 03/2012;

  The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however,The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown.We genotyped 57,657 adult individuals from the Copenhagen General Population Study of which 34,592 were eversmokers. Information on spirometry, hospital admissions, smoking behaviour, and use of nicotinic replacement therapy was recorded.In homozygous (11%), heterozygous (44%) and non-carrier (45%) eversmokers, FEV1% predicted was 94.1%, 95.3% and 96.5%, FVC% predicted was 97.1%, 97.5% and 98.3%, and FEV1/FVC was 0.770, 0.773 and 0.777 (all trend: p<0.001). Smoking interacted with genotype on FEV1% predicted and FEV1/FVC (both p<0.001). When adjusted for cumulative tobacco consumption these associations remained significant. In eversmokers, odds ratios for COPD in homozygotes versus non-carriers were 1.3 (95% CI: 1.2-1.4) for GOLD 1-4, 1.4 (1.2-1.6) for GOLD 2-4 and 1.7 (1.3-2.1) for GOLD 3-4. Corresponding value for lung cancer was 1.8 (1.2-2.6). Genotype also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers.In eversmokers, CHRNA3 rs1051730 genotype associated with reduced lung function and increased COPD severity.

• 19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus.

  Authors: Kristen N Stevens, Zachary Fredericksen, Celine M Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomäki, Carl Blomqvist [......] Marie-Rose Christiaens, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli-Matti Kosma, Jaana M Hartikainen, Ylermi Soini, Douglas F Easton, Fergus J Couch

  Cancer research. 02/2012; 72(7):1795-1803.

  The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795-803. ©2012 AACR.

• Cytochrome P450 1B1 and 2C9 Genotypes and Risk of Ischemic Vascular Disease, Cancer, and Chronic Obstructive Pulmonary Disease.

  Authors: Diljit Kaur-Knudsen, Stig E Bojesen, Børge G Nordestgaard

  Current vascular pharmacology. 01/2012;

  The aim of this review is to summarize present knowledge of genetic variation in cytochrome P450 1B1 (CYP1B1) and 2C9 (CYP2C9) genes and risk of tobacco-related cancer, female cancer, chronicThe aim of this review is to summarize present knowledge of genetic variation in cytochrome P450 1B1 (CYP1B1) and 2C9 (CYP2C9) genes and risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease. The CYP1B1 and CYP2C9 enzymes metabolize polycyclic aromatic hydrocarbons found in tobacco smoke and thereby generate disease-causing metabolites suggested to be important in tobacco-related diseases. Furthermore, CYP1B1 also metabolizes estrogen while CYP2C9 metabolizes arachidonic acid, both creating metabolites potentially important in risk of female cancer or ischemic vascular disease. Genetic variation in genes coding for CYP1B1 and CYP2C9 enzymes have shown altered enzyme activity affecting levels of metabolites and thus potentially risk of disease. So far, however, findings have been inconsistent. Recently, large studies on the association between genetic variation in CYP1B1 and CYP2C9 and risk of disease with considerable statistical power rebutted the hypotheses that these genetic variants affect risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease.

• Genome-wide association analysis identifies three new breast cancer susceptibility loci.

  Authors: Maya Ghoussaini, Olivia Fletcher, Kyriaki Michailidou, Clare Turnbull, Marjanka K Schmidt, Ed Dicks, Joe Dennis, Qin Wang, Manjeet K Humphreys, Craig Luccarini [......] Susan M Gerty, Nikki J Graham, Bruce A J Ponder, Georgia Chenevix-Trench, Paul D P Pharoah, Mark Lathrop, Alison M Dunning, Nazneen Rahman, Julian Peto, Douglas F Easton

  Nature genetics. 01/2012; 44(3):312-318.

  Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted toBreast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

• Reply from Authors re: Stacy Loeb. Use of Baseline Prostate-Specific Antigen Measurements to Personalize Prostate Cancer Screening. Eur Urol. In press. DOI: 10.1016/j.eururo.2011.11.050.

  Authors: David D Orsted, Børge G Nordestgaard, Gorm B Jensen, Peter Schnohr, Stig E Bojesen

  European urology. 12/2011;

• Short telomere length, myocardial infarction, ischemic heart disease, and early death.

  Authors: Maren Weischer, Stig E Bojesen, Richard M Cawthon, Jacob J Freiberg, Anne Tybjærg-Hansen, Børge G Nordestgaard

  Arteriosclerosis, thrombosis, and vascular biology. 12/2011; 32(3):822-9.

  We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. We measured leukocyte telomere length in 2We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7×10(-74) to P=3×10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death. Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.

• Associations between first and second primary cancers: a population-based study.

  Authors: Sune F Nielsen, Børge G Nordestgaard, Stig E Bojesen

  CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 11/2011; 184(1):E57-69.

  Patients surviving certain types of cancer are at increased risk of a second primary cancer. We tested the hypothesis that excess risk of a second primary cancer is due mainly to excess risk of itPatients surviving certain types of cancer are at increased risk of a second primary cancer. We tested the hypothesis that excess risk of a second primary cancer is due mainly to excess risk of it being the same type of cancer as the first, rather than to excess risk of it being a different type. We conducted a nationwide study using data from three dabatases for the entire Danish population (n = 7,493,705) from 1980 through 2007. For each type of cancer, we performed a nested study matching each patient with incident cancer diagnosed in that period with up to five controls who did not have the examined cancer at the time of diagnosis. We used Cox regression models to calculate individual risk estimates and meta-analysis techniques to calculate aggregated risk estimates. A total of 765,255 people had one or more diagnoses of primary cancer (total 843,118 diagnoses) during the study period. The aggregated hazard ratio (HR) for risk of any second primary cancer after any first cancer was 1.25 (95% confidence interval [CI] 1.24-1.26), with heterogeneity among cancer types. The aggregated HR for risk of a second primary cancer of the same type as the first was 2.16 (95% CI 1.98-2.34). The aggregated HR for risk of a second cancer of a different type from the first was 1.13 (95% CI 1.12-1.15). Results were similar when we excluded second primary cancers occurring within 1, 2, 5 or 10 years after the first cancer. Overall, we observed 74 significant associations among 27 types of first cancer and 27 possible types of second primary cancer. Excess risk of a second primary cancer was due mainly to a 2.2-fold risk of the second cancer being the same type as the first, whereas the risk of it being a different type was only 1.1-fold. However, heterogeneity among cancer types was substantial.

• Prostate-Specific Antigen and Long-Term Prediction of Prostate Cancer Incidence and Mortality in the General Population.

  Authors: David D Orsted, Børge G Nordestgaard, Gorm B Jensen, Peter Schnohr, Stig E Bojesen

  European urology. 11/2011;

  BACKGROUND: It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the generalBACKGROUND: It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the general population. OBJECTIVE: Determine whether baseline PSA levels predict long-term risk of PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: We examined 4383 men aged 20-94 yr from the Danish general population in the prospective Copenhagen City Heart Study. PSA was measured in plasma samples obtained in 1981-1983. MEASUREMENTS: PCa incidence and mortality as a function of baseline PSA was assessed using Kaplan-Meier plots of cumulative incidence and competing risk subhazard ratios. RESULTS AND LIMITATIONS: During 28 yr of follow-up, 170 men developed PCa, and 94 men died from PCa. Median follow-up was 18 yr (range: 0.5-28 yr). For PCa incidence, the subhazard ratio was 3.0 (95% confidence interval [CI], 1.9-4.6) for a PSA level of 1.01-2.00 ng/ml, 6.8 (95% CI, 4.2-11) for PSA 2.01-3.00 ng/ml, 6.6 (95% CI, 3.4-13) for PSA 3.01-4.00 ng/ml, 16 (95% CI, 10.4-25) for PSA 4.01-10.00 ng/ml, and 57 (95% CI, 32-104) for PSA >10.00 ng/ml versus 0.01-1.00 ng/ml. For PCa mortality, corresponding subhazard ratios were 2.2 (95% CI, 1.3-3.9), 5.1 (95% CI, 2.8-9.0), 4.2 (95% CI, 1.8-10), 7.0 (95% CI, 3.8-14), and 14 (95% CI, 6.0-32). For men with PSA levels of 0.01-1.00 ng/ml, the absolute 10-yr risk of PCa was 0.6% for ages <45 yr, 0.7% for ages 45-49 yr, 1.1% for ages 50-54 yr, 1.2% for ages 55-59 yr, 1.3% for ages 60-64 yr, 1.1% for ages 65-69 yr, 1.3% for ages 70-74 yr, and 1.5% for ages ≥75 yr; corresponding values for PSA levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively. CONCLUSIONS: Stepwise increases in PSA at first date of testing predicted a 3-57-fold increased risk of PCa, a 2-16-fold increased risk of PCa mortality, and a 35-88% absolute 10-yr risk of PCa in men with PSA levels >10.00 ng/ml. Equally important, the absolute 10-yr risk of PCa in men with PSA levels 0.01-1.00 ng/ml was only 0.6-1.5%.

• 7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium.

  Authors: Roger L Milne, Justo Lorenzo-Bermejo, Barbara Burwinkel, Núria Malats, Jose Ignacio Arias, M Pilar Zamora, Javier Benítez, Manjeet K Humphreys, Montserrat García-Closas, Stephen J Chanock [......] Carmel Apicella, John L Hopper, Alison M Dunning, Karen A Pooley, Paul D P Pharoah, Ute Hamann, Beate Pesch, Yon-Dschun Ko, Douglas F Easton, Georgia Chenevix-Trench

  Journal of medical genetics. 10/2011; 48(10):698-702.

  Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authorsUsing the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies. The authors genotyped 14,843 invasive case patients and 19,852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33,376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01). This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

• CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis.

  Authors: Maren Weischer, Ida M Heerfordt, Stig E Bojesen, Thomas Eigentler, Claus Garbe, Martin Röcken, Lisbet Rosenkrantz Hölmich, Henrik Schmidt, Helle Klyver, Lars Bastholt, Børge G Nordestgaard

  The Journal of investigative dermatology. 09/2011; 132(2):299-303.

  It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we testedIt is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.

• Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

  Authors: Roger L Milne, Ellen L Goode, Montserrat García-Closas, Fergus J Couch, Gianluca Severi, Rebecca Hein, Zachary Fredericksen, Núria Malats, M Pilar Zamora, Jose Ignacio Arias Pérez [......] Elza Khusnutdinova, Marina Bermisheva, Darya Prokofieva, Albina Farahtdinova, Janet E Olson, Xianshu Wang, Manjeet K Humphreys, Qin Wang, Georgia Chenevix-Trench, Douglas F Easton

  Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 08/2011; 20(10):2222-31.

  The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further exploreThe single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 × 10(-7)]. 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.

• Risk of thyroid cancer, brain cancer, and non-Hodgkin lymphoma after adult leukemia: a nationwide study.

  Authors: Sune F Nielsen, Stig E Bojesen, Henrik S Birgens, Børge G Nordestgaard

  Blood. 08/2011; 118(15):4062-9.

  Patients with childhood leukemia surviving into adulthood have elevated risk of developing thyroid cancer, brain cancer, and non-Hodgkin lymphoma (NHL); these risks cannot automatically bePatients with childhood leukemia surviving into adulthood have elevated risk of developing thyroid cancer, brain cancer, and non-Hodgkin lymphoma (NHL); these risks cannot automatically be extrapolated to patients surviving adult leukemia. We tested whether survivors of adult leukemia are at increased risk of developing thyroid cancer, brain cancer, and NHL. We included the entire adult Danish population (14 years of age or older), in a 28-year follow-up period from 1980 through 2007, composed of 6 542 639 persons; during this period, 18 834 developed adult leukemia, 4561 developed thyroid cancer, 13 362 developed brain cancer, and 15 967 developed NHL. In nested studies using Cox regression models on individual participant data, we found that, after adult leukemia, the multivariate adjusted hazard ratios were 4.9 (95% confidence interval [CI], 2.8-8.5) for thyroid cancer, 1.9 (95% CI, 1.2-3.1) for brain cancer, and 3.3 (95% CI, 2.5-4.4) for NHL. Corresponding hazard ratios after childhood leukemia were 10.4 (95% CI, 0.4-223) for thyroid cancer, 7.2 (95% CI, 2.0-26) for brain cancer, and 6.5 (95% CI, 0.4-110) for NHL. Patients with adult leukemia have excess risk of thyroid cancer, brain cancer, and NHL, similar to patients with childhood leukemia.

• Reply from Authors re: Ryan P. Kopp, Stephen J. Freedland, J. Kellogg Parsons. Associations of Benign Prostatic Hyperplasia With Prostate Cancer: The Debate Continues. Eur Urol. In press. doi:10.1016/j.eururo.2011.07.005.

  Authors: David D Orsted, Stig E Bojesen, Sune F Nielsen, Børge G Nordestgaard

  European urology. 07/2011;

• Association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men.

  Authors: David D Ørsted, Stig E Bojesen, Sune F Nielsen, Børge G Nordestgaard

  European urology. 06/2011; 60(4):691-8.

  Although benign prostate hyperplasia (BPH) and prostate cancer (PCa) share features such as hormone-dependent growth and response to treatment with antiandrogen therapy, BPH is generally notAlthough benign prostate hyperplasia (BPH) and prostate cancer (PCa) share features such as hormone-dependent growth and response to treatment with antiandrogen therapy, BPH is generally not considered a premalignant lesion. To determine whether clinical BPH is associated with an increased risk of PCa incidence and mortality. Using designs with individual participant data from five national registries, we studied the entire Danish male population from 1980 through 2006, a total of 3,009,258 Danish men. We collected PCa diagnoses (n=53,315), information on PCa mortality (n=25,459), and ascertained clinical BPH (not histologically proven BPH) through hospitalization (n=187,591) and/or surgery (n=77,698) from 1980 to 2006 and the use of α-adrenergic receptor antagonists (n=143,365) and/or the use of 5α-reductase inhibitors (5-ARIs) (n=47,465) from 1995 to 2006. PCa incidence and mortality was assessed for each category of clinical BPH using Kaplan-Meier plots of cumulative incidence and Cox proportional hazard ratios (HRs) adjusted for potential confounders. For the entire cohort studies, multivariate-adjusted HRs for PCa incidence were 2.22 (95% confidence interval, 2.13-2.31) in men hospitalized and 3.26 (3.03-3.50) in men operated on for clinical BPH versus general population controls. Corresponding HRs for PCa mortality were 2.00 (1.91-2.08) for hospitalization and 7.85 (7.40-8.32) for surgery. For age-matched cohort studies, corresponding HRs for PCa incidence were 3.04 (2.96-3.13) for hospitalization, 2.60 (2.47-2.73) for surgery, 4.49 (4.33-4.65) for α-adrenergic receptor antagonist use, and 2.54 (2.40-2.68) for 5-ARI use. Each category of clinical BPH has limitations, but limitations differ between the categories and therefore are unlikely to explain the results. In Danish men followed for up to 27 yr, clinical BPH was associated with a two- to three-fold increased risk of PCa incidence and with a two- to eight-fold increased risk of PCa mortality. These data should not be used to infer causality.

• Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

  Authors: Annegien Broeks, Marjanka K Schmidt, Mark E Sherman, Fergus J Couch, John L Hopper, Gillian S Dite, Carmel Apicella, Letitia D Smith, Fleur Hammet, Melissa C Southey [......] Chia-Ni Hsiung, Jyh-Cherng Yu, Shou-Tung Chen, Giu-Cheng Hsu, Ming-Feng Hou, Chiun-Sheng Huang, Hoda Anton-Culver, Argyrios Ziogas, Paul D P Pharoah, Montserrat Garcia-Closas

  Human molecular genetics. 06/2011; 20(16):3289-303.

  Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and twoBreast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

• Nicotinic acetylcholine receptor polymorphism, smoking behavior, and tobacco-related cancer and lung and cardiovascular diseases: a cohort study.

  Authors: Diljit Kaur-Knudsen, Stig E Bojesen, Anne Tybjærg-Hansen, Børge G Nordestgaard

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2011; 29(21):2875-82.

  We examined the associations between the nicotinic acetylcholine receptor polymorphism (rs1051730) on chromosome 15q25 marking the gene cluster CHRNA3-CHRNB4-CHRNA5, smoking behavior, andWe examined the associations between the nicotinic acetylcholine receptor polymorphism (rs1051730) on chromosome 15q25 marking the gene cluster CHRNA3-CHRNB4-CHRNA5, smoking behavior, and tobacco-related cancer and lung and cardiovascular diseases in the general population. Ten thousand three hundred thirty participants from the Copenhagen City Heart Study were genotyped and observed prospectively with up to 18 years of 100% complete follow-up. Smoking behavior was measured at baseline. End points were lung cancer, bladder cancer, chronic obstructive pulmonary disease, ischemic heart disease, and ischemic stroke. Multifactorially adjusted and genotype-adjusted subhazard ratios for a cumulative tobacco consumption above 40 pack-years versus 0 pack-years were 32.5 (95% CI, 12.0 to 87.7) for lung cancer, 2.2 (95% CI, 1.1 to 4.5) for bladder cancer, 9.4 (95% CI, 6.9 to 12.7) for chronic obstructive pulmonary disease, 1.5 (95% CI, 1.3 to 1.8) for ischemic heart disease, and 1.1 (95% CI, 0.8 to 1.4) for ischemic stroke. Among smoking noncarriers and homozygotes, daily tobacco consumption was 16 and 18 g/d (P < .001), cumulative tobacco consumption was 28 and 31 pack-years (P = .003), and smoking inhalation was 71.9% and 78.1% (P < .001), respectively. Multifactorially adjusted and smoking behavior-adjusted subhazard ratios for homozygotes versus noncarriers were 1.6 (95% CI, 1.1 to 2.2) for lung cancer, 1.7 (95% CI, 1.0 to 3.0) for bladder cancer, 1.3 (95% CI, 1.1 to 1.6) for chronic obstructive pulmonary disease, 0.9 (95% CI, 0.7 to 1.0) for ischemic heart disease, and 1.1 (95% CI, 0.8 to 1.4) for ischemic stroke. Although smoking is associated with major tobacco-related diseases in the general population, the nicotinic acetylcholine receptor polymorphism is associated with additional increased risk of lung cancer, bladder cancer, and chronic obstructive pulmonary disease after adjustment for smoking.

• Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study.

  Authors: Kristine H Allin, Børge G Nordestgaard, Henrik Flyger, Stig E Bojesen

  Breast cancer research : BCR. 06/2011; 13(3):R55.

  We examined whether plasma C-reactive protein (CRP) levels at the time of diagnosis of breast cancer are associated with overall survival, disease-free survival, death from breast cancer, andWe examined whether plasma C-reactive protein (CRP) levels at the time of diagnosis of breast cancer are associated with overall survival, disease-free survival, death from breast cancer, and recurrence of breast cancer. We observed 2,910 women for up to seven years after they were diagnosed with invasive breast cancer (median follow-up time was three years). Plasma levels of high-sensitivity CRP were measured at the time of diagnosis and we assessed the association between CRP levels and risk of reduced overall and disease-free survival, death from breast cancer, and recurrence of breast cancer by using the Kaplan-Meier method and Cox proportional hazards regression. During follow-up, 383 women died (225 of whom died from breast cancer) and 118 women experienced recurrence of breast cancer. Elevated CRP levels across tertiles at the time of diagnosis were associated with reduced overall and disease-free survival and with increased risk of death from breast cancer (log-rank trend for all, P < 0.001), but not with recurrence. The multifactor-adjusted hazard ratios (HR) of reduced overall survival among women in the middle and highest versus the lowest tertile of CRP were 1.30 (95% CI, 0.97 to 1.73) and 1.94 (1.48 to 2.55), respectively. Corresponding HRs of reduced disease-free survival were 1.16 (0.89 to 1.50) and 1.76 (1.38 to 2.25) and of death from breast cancer 1.22 (0.84 to 1.78) and 1.66 (1.15 to 2.41). Dividing CRP levels into octiles resulted in a stepwise increased risk of reduced overall survival (P for trend <0.001) and the multifactor-adjusted HR among women in the highest versus the lowest octile of CRP was 2.51 (1.53 to 4.12). Compared to women with CRP levels in the 0 to 25% percentile (<0.78 mg/L), the multifactor-adjusted HR of reduced overall survival among women with CRP levels ≥95% percentile (≥16.4 mg/L) was 3.58 (2.36 to 5.42). Among women with HER2-positive tumours, the multifactor-adjusted HR of reduced overall survival for the highest versus the lowest tertile of CRP was 8.63 (2.04 to 36.4). Elevated CRP levels at the time of diagnosis of breast cancer are associated with reduced overall and disease-free survival and with increased risk of death from breast cancer.

• Plasma YKL-40 levels in healthy subjects from the general population.

  Authors: Stig E Bojesen, Julia S Johansen, Børge G Nordestgaard

  Clinica chimica acta; international journal of clinical chemistry. 04/2011; 412(9-10):709-12.

  Plasma YKL-40 is a new biomarker in patients with cancer and inflammatory diseases. High plasma YKL-40 is associated with poor prognosis. Our aim was to determine reference levels in healthyPlasma YKL-40 is a new biomarker in patients with cancer and inflammatory diseases. High plasma YKL-40 is associated with poor prognosis. Our aim was to determine reference levels in healthy subjects. Plasma YKL-40 was determined in 3130 participants aged 20-80 years from the Danish general population, the Copenhagen City Heart Study. They had no known disease at time of blood sampling in 1991-1994 and remained healthy and alive during a 16-year follow-up period. In 644 participants, YKL-40 was measured again in samples taken 10 years after the first. The median plasma YKL-40 was 40 μg/L (2.5-97.5% reference levels: 14-155) with no difference between sexes. YKL-40 increased exponentially with age. For age-adjusted reference levels, the YKL-40 percentile as a function of age in years and plasma YKL-40 in μg/L was derived: percentile=100/(1+(YKL-40^-3)*(1.062^age)*5000). In subjects with two YKL-40 measurements 10 years apart, the mean increase in YKL-40 was 1.5 μg/L/year (SE: 0.2), while the mean change in the calculated age percentile was minimal (-0.3; SE: 0.1). Plasma YKL-40 increases with age within and across healthy individuals from the general population. Age-stratified or age-adjusted reference levels are important when YKL-40 test results are evaluated.