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1.  Prevalence and risk factors for foot and ankle musculoskeletal disorders experienced by nurses 
Nurses are at high risk of musculoskeletal disorders (MSDs). Although the prevalence of MSDs of the lower back, upper limbs, neck and shoulders have been reported previously in nursing, few studies have evaluated MSDs of the foot and ankle. This study evaluated the prevalence of foot and ankle MSDs in nurses and their relation to individual and workplace risk factors.
A self-administered survey incorporating the Nordic Musculoskeletal Questionnaire (NMQ) was distributed, over a nine-week period, to all eligible nurses (n = 416) working in a paediatric hospital in Brisbane, Australia. The prevalence of MSDs for each of the NMQ body regions was determined. Bivariate and multivariable logistic regression analyses were conducted to examine the relationships between activity-limiting foot/ankle MSDs and risk factors related to the individual (age, body mass index, number of existing foot conditions, smoking history, general physical health [SF36 Physical Component Scale], footwear features) or the workplace (level of nursing position, work location, average hours worked, hours worked in previous week, time since last break from work).
A 73% response rate was achieved with 304 nurses completing surveys, of whom 276 were females (91%). Mean age of the nurses was 37 years (±10), younger than the state average of 43 years. Foot/ankle MSDs were the most prevalent conditions experienced by nurses during the preceding seven days (43.8%, 95% CI 38.2-49.4%), the second most prevalent MSDs to impair physical activity (16.7%, 95% CI 13.0-21.3%), and the third most prevalent MSD, after lower-back and neck problems, during the preceding 12 months (55.3%, 95% CI 49.6-60.7%). Of the nurse and work characteristics investigated, obesity, poor general physical health, existing foot conditions and working in the intensive care unit emerged as statistically significant (p < 0.05) independent risk factors for activity-limiting foot/ankle MSDs.
Foot/ankle MSDs are common in paediatric hospital nurses and resulted in physical activity limitations in one out of every six nurses. We recommend targeted education programs regarding the prevention, self-management and treatment strategies for foot/ankle MSDs. Further research is needed into the impact of work location and extended shift durations on foot/ankle MSDs.
PMCID: PMC4061517  PMID: 24902582
2.  Activity of Decitabine in Patients with Myelodysplastic Syndrome Previously Treated with Azacitidine 
Leukemia & lymphoma  2008;49(4):690-695.
Azacitidine and decitabine are two hypomethylating agents approved by the Food and Drug Administration for the treatment of patients with myelodysplastic syndrome (MDS). The efficacy of one agent post failure of the other is unknown.
Fourteen patients with MDS post azacitidine failure/lack of response/intolerance were treated with decitabine.
Overall 3 patients achieved a complete remission and 1 patient had hematologic improvement, for an overall response rate of 28%. Of the responders 1 stopped prior 5-azacitidine due to disease progression, 2 for no response and l for severe skin toxicity. Grade 3-4 drug related side-effects were minimal. Global methylation studies in patient samples showed decrease of methylation after treatment with decitabine. As in our previous studies, there was no difference in hypomethylation between responders and non-responders.
We conclude that clinically significant responses with decitabine can be seen in patients post azacitidine failure without significant toxicity.
PMCID: PMC3702160  PMID: 18398735
azacitidine failure; decitabine; myelodysplastic syndrome
3.  Possible Genetic Predisposition to Lymphedema after Breast Cancer 
Known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicate a number of potential candidate genes to explore in relation to secondary lymphedema.
Methods and Results
We undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n=22) and those without lymphedema serving as controls (n=98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1 were selected for genotyping. Multiple SNPs within three receptor genes, VEGFR2, VEGFR3, and RORC, were associated with lymphedema defined by statistical significance (p<0.05) or extreme risk estimates (OR <0.5 or >2.0).
These provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger datasets.
PMCID: PMC3311400  PMID: 22404826
4.  Upper-body morbidity following breast cancer treatment is common, may persist longer-term and adversely influences quality of life 
Impairments in upper-body function (UBF) are common following breast cancer. However, the relationship between arm morbidity and quality of life (QoL) remains unclear. This investigation uses longitudinal data to describe UBF in a population-based sample of women with breast cancer and examines its relationship with QoL.
Australian women (n = 287) with unilateral breast cancer were assessed at three-monthly intervals, from six- to 18-months post-surgery (PS). Strength, endurance and flexibility were used to assess objective UBF, while the Disability of the Arm, Shoulder and Hand questionnaire and the Functional Assessment of Cancer Therapy-Breast questionnaire were used to assess self-reported UBF and QoL, respectively.
Although mean UBF improved over time, up to 41% of women revealed declines in UBF between six- and 18-months PS. Older age, lower socioeconomic position, treatment on the dominant side, mastectomy, more extensive lymph node removal and having lymphoedema each increased odds of declines in UBF by at least two-fold (p < 0.05). Lower baseline and declines in perceived UBF between six- and 18-months PS were each associated with poorer QoL at 18-months PS (p < 0.05).
Significant upper-body morbidity is experienced by many following breast cancer treatment, persisting longer term, and adversely influencing the QoL of breast cancer survivors.
PMCID: PMC2940926  PMID: 20804558
5.  The population approach to falls injury prevention in older people: findings of a two community trial 
BMC Public Health  2010;10:79.
There is a sound rationale for the population-based approach to falls injury prevention but there is currently insufficient evidence to advise governments and communities on how they can use population-based strategies to achieve desired reductions in the burden of falls-related injury. The aim of the study was to quantify the effectiveness of a streamlined (and thus potentially sustainable and cost-effective), population-based, multi-factorial falls injury prevention program for people over 60 years of age.
Population-based falls-prevention interventions were conducted at two geographically-defined and separate Australian sites: Wide Bay, Queensland, and Northern Rivers, NSW. Changes in the prevalence of key risk factors and changes in rates of injury outcomes within each community were compared before and after program implementation and changes in rates of injury outcomes in each community were also compared with the rates in their respective States.
The interventions in neither community substantially decreased the rate of falls-related injury among people aged 60 years or older, although there was some evidence of reductions in occurrence of multiple falls reported by women. In addition, there was some indication of improvements in fall-related risk factors, but the magnitudes were generally modest.
The evidence suggests that low intensity population-based falls prevention programs may not be as effective as those that are intensively implemented.
PMCID: PMC2836986  PMID: 20167124
6.  Does quality of life among breast cancer survivors one year after diagnosis differ depending on urban and non-urban residence? A comparative study 
This study examined the quality of life (QOL), measured by the Functional Assessment of Cancer Therapy (FACT) questionnaire, among urban (n = 277) and non-urban (n = 323) breast cancer survivors and women from the general population (n = 1140) in Queensland, Australia.
Population-based samples of breast cancer survivors aged < 75 years who were 12 months post-diagnosis and similarly-aged women from the general population were recruited between 2002 and 2007.
Age-adjusted QOL among urban and non-urban breast cancer survivors was similar, although QOL related to breast cancer concerns was the weakest domain and was lower among non-urban survivors than their urban counterparts (36.8 versus 40.4, P < 0.01). Irrespective of residence, breast cancer survivors, on average, reported comparable scores on most QOL scales as their general population peers, although physical well-being was significantly lower among non-urban survivors (versus the general population, P < 0.01). Overall, around 20%-33% of survivors experienced lower QOL than peers without the disease. The odds of reporting QOL below normative levels were increased more than two-fold for those who experienced complications following surgery, reported upper-body problems, had higher perceived stress levels and/or a poor perception of handling stress (P < 0.01 for all).
Results can be used to identify subgroups of women at risk of low QOL and to inform components of tailored recovery interventions to optimize QOL for these women following cancer treatment.
PMCID: PMC2821367  PMID: 20059768
7.  Flexible Frames and Control Sampling in Case-Control Studies: Weighters (Survey Statisticians) Versus Anti-Weighters (Epidemiologists) 
The American statistician  2008;62(4):307-313.
We propose two innovations in statistical sampling for controls to enable better design of population-based case-control studies. The main innovation leads to novel solutions, without using weights, of the difficult and long-standing problem of selecting a control from persons in a household. Another advance concerns the drawing (at the outset) of the households themselves and involves random-digit dialing with atypical use of list-assisted sampling. A common element throughout is that one capitalizes on flexibility (not broadly available in usual survey settings) in choosing the frame, which specifies the population of persons from which both cases and controls come.
PMCID: PMC2744085  PMID: 19759839
Bias; List-assisted sampling; Population-based case-control studies; Random-digit dialing; Respondent selection within households
8.  Genome-wide association study identifies novel breast cancer susceptibility loci 
Easton, Douglas F. | Pooley, Karen A. | Dunning, Alison M. | Pharoah, Paul D. P. | Thompson, Deborah | Ballinger, Dennis G. | Struewing, Jeffery P. | Morrison, Jonathan | Field, Helen | Luben, Robert | Wareham, Nicholas | Ahmed, Shahana | Healey, Catherine S. | Bowman, Richard | Meyer, Kerstin B. | Haiman, Christopher A. | Kolonel, Laurence K. | Henderson, Brian E. | Marchand, Loic Le | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Odefrey, Fabrice | Shen, Chen-Yang | Wu, Pei-Ei | Wang, Hui-Chun | Eccles, Diana | Evans, D. Gareth | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Seal, Sheila | Stratton, Michael R. | Rahman, Nazneen | Chenevix-Trench, Georgia | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Garcia-Closas, Montserrat | Brinton, Louise | Chanock, Stephen | Lissowska, Jolanta | Peplonska, Beata | Nevanlinna, Heli | Fagerholm, Rainer | Eerola, Hannaleena | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Hall, Per | Wedren, Sara | Liu, Jianjun | Low, Yen-Ling | Bogdanova, Natalia | Schürmann, Peter | Dörk, Thilo | Tollenaar, Rob A. E. M. | Jacobi, Catharina E. | Devilee, Peter | Klijn, Jan G. M. | Sigurdson, Alice J. | Doody, Michele M. | Alexander, Bruce H. | Zhang, Jinghui | Cox, Angela | Brock, Ian W. | MacPherson, Gordon | Reed, Malcolm W. R. | Couch, Fergus J. | Goode, Ellen L. | Olson, Janet E. | Meijers-Heijboer, Hanne | van den Ouweland, Ans | Uitterlinden, André | Rivadeneira, Fernando | Milne, Roger L. | Ribas, Gloria | Gonzalez-Neira, Anna | Benitez, Javier | Hopper, John L. | McCredie, Margaret | Southey, Melissa | Giles, Graham G. | Schroen, Chris | Justenhoven, Christina | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana | Day, Nicholas E. | Cox, David R. | Ponder, Bruce A. J. | Luccarini, Craig | Conroy, Don | Shah, Mitul | Munday, Hannah | Jordan, Clare | Perkins, Barbara | West, Judy | Redman, Karen | Driver, Kristy | Aghmesheh, Morteza | Amor, David | Andrews, Lesley | Antill, Yoland | Armes, Jane | Armitage, Shane | Arnold, Leanne | Balleine, Rosemary | Begley, Glenn | Beilby, John | Bennett, Ian | Bennett, Barbara | Berry, Geoffrey | Blackburn, Anneke | Brennan, Meagan | Brown, Melissa | Buckley, Michael | Burke, Jo | Butow, Phyllis | Byron, Keith | Callen, David | Campbell, Ian | Chenevix-Trench, Georgia | Clarke, Christine | Colley, Alison | Cotton, Dick | Cui, Jisheng | Culling, Bronwyn | Cummings, Margaret | Dawson, Sarah-Jane | Dixon, Joanne | Dobrovic, Alexander | Dudding, Tracy | Edkins, Ted | Eisenbruch, Maurice | Farshid, Gelareh | Fawcett, Susan | Field, Michael | Firgaira, Frank | Fleming, Jean | Forbes, John | Friedlander, Michael | Gaff, Clara | Gardner, Mac | Gattas, Mike | George, Peter | Giles, Graham | Gill, Grantley | Goldblatt, Jack | Greening, Sian | Grist, Scott | Haan, Eric | Harris, Marion | Hart, Stewart | Hayward, Nick | Hopper, John | Humphrey, Evelyn | Jenkins, Mark | Jones, Alison | Kefford, Rick | Kirk, Judy | Kollias, James | Kovalenko, Sergey | Lakhani, Sunil | Leary, Jennifer | Lim, Jacqueline | Lindeman, Geoff | Lipton, Lara | Lobb, Liz | Maclurcan, Mariette | Mann, Graham | Marsh, Deborah | McCredie, Margaret | McKay, Michael | McLachlan, Sue Anne | Meiser, Bettina | Milne, Roger | Mitchell, Gillian | Newman, Beth | O'Loughlin, Imelda | Osborne, Richard | Peters, Lester | Phillips, Kelly | Price, Melanie | Reeve, Jeanne | Reeve, Tony | Richards, Robert | Rinehart, Gina | Robinson, Bridget | Rudzki, Barney | Salisbury, Elizabeth | Sambrook, Joe | Saunders, Christobel | Scott, Clare | Scott, Elizabeth | Scott, Rodney | Seshadri, Ram | Shelling, Andrew | Southey, Melissa | Spurdle, Amanda | Suthers, Graeme | Taylor, Donna | Tennant, Christopher | Thorne, Heather | Townshend, Sharron | Tucker, Kathy | Tyler, Janet | Venter, Deon | Visvader, Jane | Walpole, Ian | Ward, Robin | Waring, Paul | Warner, Bev | Warren, Graham | Watson, Elizabeth | Williams, Rachael | Wilson, Judy | Winship, Ingrid | Young, Mary Ann | Bowtell, David | Green, Adele | deFazio, Anna | Chenevix-Trench, Georgia | Gertig, Dorota | Webb, Penny
Nature  2007;447(7148):1087-1093.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
PMCID: PMC2714974  PMID: 17529967
9.  A Genome Wide Linkage Search for Breast Cancer Susceptibility Genes 
Genes, chromosomes & cancer  2006;45(7):646-655.
Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.
PMCID: PMC2714969  PMID: 16575876
10.  Epidemiology of basal-like breast cancer 
Risk factors for the newly identified “intrinsic” breast cancer subtypes (luminal A, luminal B, basal-like and human epidermal growth factor receptor 2-positive/estrogen receptor-negative) were determined in the Carolina Breast Cancer Study, a population-based, case–control study of African-American and white women. Immunohistochemical markers were used to subtype 1,424 cases of invasive and in situ breast cancer, and case subtypes were compared to 2,022 controls. Luminal A, the most common subtype, exhibited risk factors typically reported for breast cancer in previous studies, including inverse associations for increased parity and younger age at first full-term pregnancy. Basal-like cases exhibited several associations that were opposite to those observed for luminal A, including increased risk for parity and younger age at first term full-term pregnancy. Longer duration breastfeeding, increasing number of children breastfed, and increasing number of months breastfeeding per child were each associated with reduced risk of basal-like breast cancer, but not luminal A. Women with multiple live births who did not breastfeed and women who used medications to suppress lactation were at increased risk of basal-like, but not luminal A, breast cancer. Elevated waist-hip ratio was associated with increased risk of luminal A in postmenopausal women, and increased risk of basal-like breast cancer in pre- and postmenopausal women. The prevalence of basal-like breast cancer was highest among premenopausal African-American women, who also showed the highest prevalence of basal-like risk factors. Among younger African-American women, we estimate that up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity.
PMCID: PMC2443103  PMID: 17578664
Breast cancer subtypes; molecular epidemiology
11.  Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation 
Breast Cancer Research  2007;9(3):R36.
Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS).
In this report, we evaluated risk factors for invasive breast cancer classified according to the presence or absence of the ESR1 A908G mutation in the CBCS, a population-based case-control study of breast cancer among younger and older white and African-American women in North Carolina. Of the 653 breast tumors evaluated, 37 were ESR1 A908G mutation-positive and 616 were mutation-negative.
ESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.15 to 6.28), whereas mutation-negative breast cancer was not. Comparison of the two case subgroups supported this finding (OR = 2.65, 95% CI = 1.15 to 6.09). There was also the suggestion that longer duration of oral contraceptive (OC) use (OR = 3.73, 95% CI = 1.16 to 12.03; Ptrend = 0.02 for use of more than 10 years) and recent use of OCs (OR = 3.63, 95% CI = 0.80 to 16.45; Ptrend = 0.10 for use within 10 years) were associated with ESR1 A908G mutation-positive breast cancer; however, ORs for comparison of the two case subgroups were not statistically significant. Hormone replacement therapy use was inversely correlated with mutation-negative breast cancer, but the effect on mutation-positive cancer was unclear due to the small number of postmenopausal cases whose tumors carried the mutation. Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% CI = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74).
These preliminary results suggest that OCs may interact with the ESR1 A908G mutant receptor to drive the development of some breast tumors.
PMCID: PMC1929100  PMID: 17553133
12.  The estrogen receptor-α A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study 
Breast Cancer Research  2005;7(6):R871-R880.
Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor-α (ER-α), occur during breast cancer development. A point mutation in ER-α (nucleotide A908G), producing an amino acid change from lysine to arginine at codon 303 (K303R) results in receptor hypersensitivity to estrogen. This mutation was initially reported in one-third of hyperplastic benign breast lesions, although several recent studies failed to detect it in benign or malignant breast tissues.
We screened 653 microdissected, newly diagnosed invasive breast tumors from patients in the Carolina Breast Cancer Study, a population-based case-control study of breast cancer in African American and white women in North Carolina, for the presence of the ER-α A908G mutation by using single-strand conformational polymorphism (SSCP) analysis and 33P-cycle sequencing.
We detected the ER-α A908G mutation in 37 of 653 (5.7%) breast tumors. The absence of this mutation in germline DNA confirmed it to be somatic. Three tumors exhibited only the mutant G base at nucleotide 908 on sequencing, indicating that the wild-type ER-α allele had been lost. The ER-α A908G mutation was found more frequently in higher-grade breast tumors (odds ratio (OR) 2.83; 95% confidence interval (CI) 1.09 to 7.34, grade II compared with grade I), and in mixed lobular/ductal tumors (OR 2.10; 95% CI 0.86 to 5.12) compared with ductal carcinomas, although the latter finding was not statistically significant.
This population-based study, the largest so far to screen for the ER-α A908G mutation in breast cancer, confirms the presence of the mutant in invasive breast tumors. The mutation was associated with higher tumor grade and mixed lobular/ductal breast tumor histology.
PMCID: PMC1410768  PMID: 16280033
13.  Re-interpreting the data on the cost and effectiveness of population screening for colorectal cancer in Australia 
Three studies report estimates of the cost and effectiveness of alternate strategies for screening the average-risk Australian population for colorectal cancer. The options considered are faecal occult blood testing, double contrast barium enema, sigmoidoscopy and colonoscopy. At present, there is no consensus over which screening method is optimal by the economic criterion. Also, the existing studies report a mixture of average and incremental cost-effectiveness ratios derived from data collected between 1994 and 2002. We suggest average cost-effectiveness ratios are not useful for decision-making and illustrate how they differ from the preferred incremental cost-effectiveness ratio. We then update the cost data reported in the three studies to 2002 prices and calculate incremental cost-effectiveness ratios where not previously available. Our re-analysis of one study contradicts the conclusions drawn by the authors, who had only calculated average cost-effectiveness ratios. In particular, we find their recommendation of population screening with colonoscopy would cause, annually, between 33 and 1,322 years of life to be lost and between $M17 and $M87 to be wasted. Based on updated cost data and the incremental analysis, our findings indicate that population screening using biennial faecal occult blood testing ($39,459 per life-year gained), annual faecal occult blood testing ($30,556 per life-year gained) and colonoscopy ($26,587 per life-year gained) are cost-effective. Hence, the decision over which method of screening is optimal remains ambiguous across the three studies. We recommend policy-makers choose the study they believe produces the most accurate estimates of cost and health effect, identify their willingness to pay for health benefits and consider other issues relevant to the decision.
PMCID: PMC1173078  PMID: 15904536
14.  The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers 
Breast Cancer Research  2004;7(2):R176-R183.
The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer.
A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size.
There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers.
The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.
PMCID: PMC1064126  PMID: 15743497
AR; BRCA1; BRCA2; modifier
15.  Polychlorinated biphenyls, cytochrome P450 1A1 (CYP1A1) polymorphisms, and breast cancer risk among African American women and white women in North Carolina: a population-based case-control study 
Breast Cancer Research  2004;7(1):R12-R18.
Epidemiologic studies have not shown a strong relationship between blood levels of polychlorinated biphenyls (PCBs) and breast cancer risk. However, two recent studies showed a stronger association among postmenopausal white women with the inducible M2 polymorphism in the cytochrome P450 1A1 (CYP1A1) gene.
In a population-based case-control study, we evaluated breast cancer risk in relation to PCBs and the CYP1A1 polymorphisms M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C), M3 (CYP1A1*3), and M4 (CYP1A1*4). The study population consisted of 612 patients (242 African American, 370 white) and 599 controls (242 African American, 357 white).
There was no evidence of strong joint effects between CYP1A1 M1-containing genotypes and total PCBs in African American or white women. Statistically significant multiplicative interactions were observed between CYP1A1 M2-containing genotypes and elevated plasma total PCBs among white women (P value for likelihood ratio test = 0.02). Multiplicative interactions were also observed between CYP1A1 M3-containing genotypes and elevated total PCBs among African American women (P value for likelihood ratio test = 0.10).
Our results confirm previous reports that CYP1A1 M2-containing genotypes modify the association between PCB exposure and risk of breast cancer. We present additional evidence suggesting that CYP1A1 M3-containing genotypes modify the effects of PCB exposure among African American women. Additional studies are warranted, and meta-analyses combining results across studies will be needed to generate more precise estimates of the joint effects of PCBs and CYP1A1 genotypes.
PMCID: PMC1064095  PMID: 15642161
breast cancer; CYP1A1; polychlorinated biphenyls
16.  Birthweight, parental age, birth order and breast cancer risk in African-American and white women: a population-based case–control study 
Breast Cancer Research  2004;6(6):R656-R667.
Much recent work has focused on hypotheses that very early life exposures influence adult cancer risk. For breast cancer it has been hypothesized that high in utero estrogen exposure may increase risk.
We used data from the Carolina Breast Cancer Study, a population-based case–control study of incident breast cancer in North Carolina, to examine associations for three possible surrogates of high prenatal estrogen exposure: weight at birth, maternal age, and birth order. We also examined paternal age. Birthweight analyses were conducted for white and African-American women born in North Carolina on or after 1949 (196 cases, 167 controls). Maternal age was analyzed for US born participants younger than 49 years of age (280 cases, 236 controls).
There was a weak inverse association between birthweight in the highest tertile and breast cancer overall (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.4–1.2), although associations differed by race (OR 0.5, 95% CI 0.2–1.0, and OR 1.0, 95% CI 0.5–2.1 for African-American and white women, respectively). For maternal age there was an approximately threefold increase in risk in women whose mothers were older than 22 years of age, relative to 19–22 years of age, when the women were born. After adjustment for maternal age, older paternal age increased risk in the oldest and youngest age categories (relative to 23–27 years of age at the woman's birth: OR 1.6, 95% CI 0.8–3.1 for age 15–22 years; OR 1.2, 95% CI 0.7–2.2 for age 28–34 years; and OR 1.5, 95% CI 0.7–3.2 for age 35–56 years). There was no association with older paternal age for white women alone. After adjustment for maternal age (265 cases, 224 controls), a birth order of fifth or higher relative to first had an inverse association with breast cancer for women younger than 49 years old (OR 0.6, 95% CI 0.3–1.3).
Although the CIs are wide, these results lend support to the possibility that the prenatal period is important for subsequent breast cancer risk, but they do not support the estrogen hypothesis as a unifying theory for the influence of this period.
PMCID: PMC1064078  PMID: 15535848
African-American; birthweight; breast cancer; maternal age; prenatal
17.  Cigarette smoking, cytochrome P4501A1 polymorphisms, and breast cancer among African-American and white women 
Breast Cancer Research  2004;6(4):R460-R473.
Previous epidemiologic studies suggest that women with variant cytochrome P4501A1 (CYP1A1) genotypes who smoke cigarettes are at increased risk for breast cancer.
We evaluated the association of breast cancer with CYP1A1 polymorphisms and cigarette smoking in a population-based, case–control study of invasive breast cancer in North Carolina. The study population consisted of 688 cases (271 African Americans and 417 whites) and 702 controls (285 African Americans and 417 whites). Four polymorphisms in CYP1A1 were genotyped using PCR/restriction fragment length polymorphism analysis: M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C), M3 (CYP1A1*3), and M4 (CYP1A1*4)
No associations were observed for CYP1A1 variant alleles and breast cancer, ignoring smoking. Among women who smoked for longer than 20 years, a modest positive association was found among women with one or more M1 alleles (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2–3.5) but not among women with non-M1 alleles (OR = 1.2, 95% CI = 0.9–1.6). Odds ratios for smoking longer than 20 years were higher among African-American women with one or more M3 alleles (OR = 2.5, 95% CI = 0.9–7.1) compared with women with non-M3 alleles (OR = 1.3, 95% CI = 0.8–2.2). ORs for smoking in white women did not differ appreciably based upon M2 or M4 genotypes.
Cigarette smoking increases breast cancer risk in women with CYP1A1 M1 variant genotypes and in African-American women with CYP1A1 M3 variant genotypes, but the modifying effects of the CYP1A1 genotype are quite weak.
PMCID: PMC468667  PMID: 15217514
African Americans; breast cancer; cytochrome P4501A1
18.  No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer 
Breast Cancer Research  2002;4(6):R15.
There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study.
The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression.
The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age.
The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women.
PMCID: PMC137935  PMID: 12473176
ataxia-telangiectasia mutated gene; breast cancer; variant

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