-
S E Bojesen,
K A Pooley,
S E Johnatty,
J Beesley,
K Michailidou,
J P Tyrer,
S L Edwards,
H A Pickett,
H C Shen,
C E Smart, [......],
P Hillemanns,
R Winqvist,
M Durst,
P Devilee,
I Runnebaum,
A Jakubowska,
J Lubinski,
A Mannermaa,
R Butzow,
others
[show abstract]
[hide abstract]
ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed approximately 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10(-14)) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
01/2013: pages 371-84;
-
[show abstract]
[hide abstract]
ABSTRACT: Background:We aimed to assess whether 2D : 4D measures are associated with breast cancer risk.Methods:We derived the ratio of the lengths of the index and ring fingers (2D : 4D), and right minus left 2D : 4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D : 4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D : 4D measures and age at menarche and menopause.Results:We found a direct association between left 2D : 4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D : 4D and breast cancer risk. Among breast cancer cases, both right 2D : 4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D : 4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause.Conclusion:Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.
British Journal of Cancer 09/2012; 107(9):1631-6. · 5.04 Impact Factor
-
Z. Kote-Jarai,
A. Amin Al Olama,
D. Leongamornlert,
M. Tymrakiewicz,
E. Saunders,
M. Guy,
G. G. Giles,
G. Severi,
M. Southey, J. L. Hopper, [......],
N. Brown,
S. Benlloch,
E. Castro,
N. Mahmud,
L. O’Brien,
A. Hall,
E. Sawyer,
R. Wilkinson,
D. F. Easton,
R. A. Eeles
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these
(rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring.
To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples
from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197
and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant
association with PrCa was with a previously unidentified SNP, rs17632542 (combined P=3.9×10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and
10,681 controls (combined P=1.9×10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the
protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.
Human Genetics 04/2012; 129(6):687-694. · 5.07 Impact Factor
-
D J Park,
F Lesueur,
T Nguyen-Dumont,
M Pertesi,
F Odefrey,
F Hammet,
S L Neuhausen,
E M John,
I L Andrulis,
M B Terry, [......],
N Hoogerbrugge,
A Barroso,
A Osorio,
G G Giles,
P Devilee,
J Benitez, J L Hopper,
S V Tavtigian,
D E Goldgar,
M C Southey
[show abstract]
[hide abstract]
ABSTRACT: An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.
The American Journal of Human Genetics 04/2012; 90(4):734-9. · 10.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Growing pains (GP) is a prevalent familial childhood disorder of unknown aetiology. Familial occurrence of GP, and individual and familial association of GP with restless legs syndrome (RLS) has been reported.
We applied a twin family design to search for evidence of genetic susceptibility to GP, and for a genetic relationship between GP and RLS. The parents of 1843 twin pairs aged 3-16 years were administered a questionnaire, which identified 88 pairs with at least one twin individual fulfilling criteria for GP. Standard questionnaires for history of GP and RLS were completed for these twin pairs, their siblings and parents.
Twenty-five of 34 monozygotic (MZ) pairs were concordant for GP, compared with 12 of the 54 dizygotic (DZ) pairs. The casewise concordance was 0.85 and 0.36 for MZ and DZ pairs, respectively (p < 0.001). The lifetime GP prevalence for relatives of twins with GP was 51% for non-twin siblings, 47% for parents. Twenty-three percent of twin individuals with GP met RLS criteria compared with 8% of twin individuals without GP (p = 0.03). Of the twins with GP concordance, 19% met RLS criteria compared with 2% of twins with GP discordance (p = 0.01). In two MZ pairs, one had GP and the other RLS. The lifetime prevalence of RLS was 40% for mothers, and 24% for fathers and 18% for non-twin siblings.
This first twin family study of GP provides evidence for a genetic aetiology and for a genetic relationship to RLS.
European journal of pain (London, England) 03/2012; 16(9):1224-31. · 3.37 Impact Factor
-
S. Jiao,
L. Hsu,
S. Berndt,
S. Bezieau,
H. Brenner,
D. Buchanan,
B. J. Caan,
P. T. Campbell,
C. S. Carlson,
G. Casey, [......],
J. D. Potter,
C. Qu,
S. A. Rosse,
R. E. Schoen,
F. R. Schumacher,
D. Seminara,
M. L. Slattery,
C. M. Ulrich,
B. W. Zanke,
U. Peters
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19x10(-8). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51x10(-6); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.
PLoS ONE 01/2012; 7(12):e52535. · 4.09 Impact Factor
-
J L Hopper,
M A Jenkins,
J G Dowty,
G S Dite,
C Apicella,
L Keogh,
A K Win,
J P Young,
D Buchanan,
M D Walsh, [......],
L Baglietto,
G Severi,
K A Phillips,
E M Wong,
A Dobrovic,
P Waring,
I Winship,
S J Ramus,
G G Giles,
M C Southey
[show abstract]
[hide abstract]
ABSTRACT: Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.
Pathology 12/2011; 44(2):89-98. · 2.38 Impact Factor
-
K N Stevens,
M Garcia-Closas,
Z Fredericksen,
M Kosel,
V S Pankratz, J L Hopper,
G S Dite,
C Apicella,
M C Southey,
M K Schmidt, [......],
K-Y Yoo,
D-Y Noh,
S Sangrajrang,
V Gabrieau,
P Brennan,
J McKay,
H Anton-Culver,
A Ziogas,
F J Couch,
D F Easton
[show abstract]
[hide abstract]
ABSTRACT: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.
A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).
Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).
Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
British Journal of Cancer 12/2011; 105(12):1934-9. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: B vitamins and related enzymes involved in one-carbon metabolism are necessary for DNA replication, DNA repair and regulation of gene expression. Disruption of one-carbon mechanism may affect cancer risk. We investigated prospectively the relationship between dietary intakes of methionine, B vitamins associated with one-carbon metabolism and risk of lung cancer.
The Melbourne Collaborative Cohort Study recruited 41,514 men and women aged 40-69 years between 1990 and 1994. During follow-up of 14,595 men and 22,451 women for an average of 15 years, we ascertained 348 incident lung cancers. Dietary intake of B vitamins and methionine was estimated from a 121-item food frequency questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression.
In current smokers, dietary intake of riboflavin was inversely associated with lung cancer risk (HR=0.53; 95% CI: 0.29-0.94, fifth versus first quintile; P-linear trend=0.01). No associations were found for former or never smokers or for dietary intake of any of the other B vitamins or methionine.
Overall, we found little evidence of an association between B vitamins or methionine and lung cancer risk. The weak inverse association between riboflavin and lung cancer risk in current smokers needs further investigation.
European journal of clinical nutrition 08/2011; 66(2):182-7. · 3.07 Impact Factor
-
T J Key,
P N Appleby,
G K Reeves,
A W Roddam,
K J Helzlsouer,
A J Alberg,
D E Rollison,
J F Dorgan,
L A Brinton,
K Overvad, [......],
S Akiba,
R G Stevens,
K Neriishi,
C E Land,
J A Cauley,
Li Yung Lui,
Steven R Cummings,
M J Gunter,
T E Rohan,
H D Strickler
[show abstract]
[hide abstract]
ABSTRACT: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.
Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.
Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.
Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.
British Journal of Cancer 08/2011; 105(5):709-22. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.
Breast Cancer Research and Treatment 08/2011; 130(3):1057-61. · 4.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The ratio of the lengths of index and ring fingers (2D:4D) is a marker of prenatal exposure to sex hormones, with low 2D:4D being indicative of high prenatal androgen action. Recent studies have reported a strong association between 2D:4D and risk of prostate cancer.
A total of 6258 men participating in the Melbourne Collaborative Cohort Study had 2D:4D assessed. Of these men, we identified 686 incident prostate cancer cases. Hazard ratios (HRs) and confidence intervals (CIs) were estimated for a standard deviation increase in 2D:4D.Results:No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92-1.08 for right, 0.93-1.08 for left). We observed a weak inverse association between 2D:4D and risk of prostate cancer for age <60, however 95% CIs included unity for all observed ages.
Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.
British Journal of Cancer 07/2011; 105(3):438-40. · 5.04 Impact Factor
-
T J Key,
P N Appleby,
G K Reeves,
A W Roddam,
K J Helzlsouer,
A J Alberg,
D E Rollison,
J F Dorgan,
L A Brinton,
K Overvad, [......],
S Akiba,
R G Stevens,
K Neriishi,
C E Land,
J A Cauley,
Li Yung Lui,
Steven R Cummings,
M J Gunter,
T E Rohan,
H D Strickler
[show abstract]
[hide abstract]
ABSTRACT: Background: Methods: Results: Conclusion: Materials and methods Results Discussion Conclusions Conflict of interest References Acknowledgements Figures and TablesBackground: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.
British Journal of Cancer 07/2011; 105(5):709-722. · 5.04 Impact Factor
-
A K Win,
J G Dowty,
D R English,
P T Campbell,
J P Young,
I Winship,
F A Macrae,
L Lipton,
S Parry,
G P Young, [......],
G Casey,
J A Baron,
N M Lindor,
S N Thibodeau,
P A Newcomb,
J D Potter,
L Le Marchand,
S Gallinger, J L Hopper,
M A Jenkins
[show abstract]
[hide abstract]
ABSTRACT: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.
A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.
During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).
Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.
British Journal of Cancer 05/2011; 105(1):162-9. · 5.04 Impact Factor
-
A K Win,
J G Dowty,
D R English,
P T Campbell,
J P Young,
I Winship,
F A Macrae,
L Lipton,
S Parry,
G P Young, [......],
G Casey,
J A Baron,
N M Lindor,
S N Thibodeau,
P A Newcomb,
J D Potter,
L Le Marchand,
S Gallinger, J L Hopper,
M A Jenkins
[show abstract]
[hide abstract]
ABSTRACT: Background: Methods: Results: Conclusion: Materials and methods Results Discussion Conflict of interest References Acknowledgements Figures and TablesBackground: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.
British Journal of Cancer 05/2011; 105(1):162-169. · 5.04 Impact Factor
-
Z Kote-Jarai,
A Amin Al Olama,
D Leongamornlert,
M Tymrakiewicz,
E Saunders,
M Guy,
G G Giles,
G Severi,
M Southey, J L Hopper, [......],
N Brown,
S Benlloch,
E Castro,
N Mahmud,
L O'Brien,
A Hall,
E Sawyer,
R Wilkinson,
D F Easton,
R A Eeles
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.
Human Genetics 04/2011; 129(6):687-94. · 5.07 Impact Factor
-
B E Kiely,
M L Friedlander,
R L Milne,
L Stanhope,
P Russell,
M A Jenkins,
P Weideman,
S A McLachlan,
P Grant, J L Hopper,
K A Phillips
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. "Adequate" surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. "Adequate" pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2-167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07-1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87-0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06-1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4-6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.
Familial Cancer 03/2011; 10(3):505-14. · 1.30 Impact Factor
-
M C Southey,
S J Ramus,
J G Dowty,
L D Smith,
A A Tesoriero,
E E M Wong,
G S Dite,
M A Jenkins,
G B Byrnes,
I Winship,
K-A Phillips,
G G Giles, J L Hopper
[show abstract]
[hide abstract]
ABSTRACT: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.
We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.
The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90).
Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.
British Journal of Cancer 02/2011; 104(6):903-9. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer.
Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression.
During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01).
Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.
British Journal of Cancer 02/2011; 104(3):524-31. · 5.04 Impact Factor
-
K. M. Im,
T. Kirchhoff,
X. Wang,
T. Green,
C. Y. Chow,
J. Vijai,
J. Korn,
M. M. Gaudet,
Z. Fredericksen,
V. Shane Pankratz, [......],
R. J. Klein,
M. J. Daly,
E. Friedman,
M. Dean,
A. G. Clark,
D. M. Altshuler,
A. C. Antoniou,
F. J. Couch,
K. Offit,
B. Gold
[show abstract]
[hide abstract]
ABSTRACT: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
Human genetics. 01/2011; 130(5):685-99.
