RESUMO
BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.
Assuntos
Neoplasias da Mama/metabolismo , Receptores de Estrogênio/deficiência , Receptores de Progesterona/deficiência , Reprodução/fisiologia , Adulto , Austrália/epidemiologia , Aleitamento Materno/estatística & dados numéricos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , California/epidemiologia , Estudos de Casos e Controles , Anticoncepcionais Orais/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Ontário/epidemiologia , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Sistema de Registros , Fatores de RiscoRESUMO
BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.
Assuntos
Neoplasias da Mama/epidemiologia , Simulação por Computador , Modelos Estatísticos , Adulto , Idoso , Algoritmos , Austrália , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Saúde da Família , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Sistema de Registros , Medição de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. METHODS: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. RESULTS: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. CONCLUSION: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.
Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , RiscoRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/patologia , Genes BRCA1 , Mutação em Linhagem Germinativa , Adulto , Fatores Etários , Neoplasias da Mama/diagnóstico , Carcinoma/diagnóstico , Análise Mutacional de DNA , Saúde da Família , Feminino , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Carga Tumoral , MulheresRESUMO
BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
Assuntos
Neoplasias da Mama/enzimologia , Predisposição Genética para Doença , Variação Genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Classe I de Fosfatidilinositol 3-Quinases , Feminino , HumanosRESUMO
BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.
Assuntos
Idade de Início , Neoplasias da Mama/genética , Família , Genes BRCA1 , Genes BRCA2 , Mutação , Adulto , Neoplasias da Mama/epidemiologia , Saúde da Família , Feminino , Humanos , Mães , Risco , IrmãosRESUMO
BACKGROUND: A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These studies relied on visual sizing of alleles on electrophoretic gels and may have underreported rare alleles. We determined whether this hypothesis applied to early-onset breast cancer by using a new method to size minisatellite alleles. METHODS: We conducted a population-based, case-control-family study of 249 Australian women under 40 years old at diagnosis of a first primary breast cancer and 234 randomly selected women, frequency matched for age. We sized HRAS1 minisatellite alleles with an Applied Biosystems model 373 automated DNA sequencer and GENESCAN(TM) software. All P values are two-sided. RESULTS: We found no association of rare alleles with breast cancer, before or after adjustment for risk factors and irrespective of how their effects were modeled (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P =.8). The rare allele frequency was 0. 173 (95% CI = 0.149-0.197), three times the pooled estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P<.001), and was similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects, 0.169 (95% CI = 0.135-0.203) (P =.7). CONCLUSION: There was no support for an association between rare HRAS1 alleles and the risk of early-onset breast cancer, despite 80% power to detect effects of the magnitude of those associations (1.7-fold) previously suggested. IMPLICATIONS: The question of whether cancer risk is associated with rare minisatellite HRAS1 alleles needs to be revisited with the use of new methods that have a greater ability to distinguish rare alleles from similarly sized common alleles.
Assuntos
Alelos , Neoplasias da Mama/genética , Repetições Minissatélites , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Austrália , Estudos de Casos e Controles , Feminino , Humanos , Razão de Chances , Distribuição AleatóriaRESUMO
BACKGROUND: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed. RESULTS: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years. CONCLUSIONS: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Polimorfismo Genético , Esteroide 17-alfa-Hidroxilase/genética , Adulto , Fatores Etários , Idade de Início , Alelos , Austrália , Estudos de Casos e Controles , Primers do DNA , DNA de Neoplasias/análise , Feminino , Genes BRCA1/genética , Genes Supressores de Tumor/genética , Genótipo , Humanos , Modelos Logísticos , Mutação , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , RiscoRESUMO
BACKGROUND: We conducted a population-based, case-control-family study to determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length (CAGn) was a risk factor for early-onset breast cancer in the Australian population. METHODS: Case subjects under 40 years of age at diagnosis of a first primary breast cancer and age-matched control subjects were interviewed to assess family history and other risk factors. AR CAGn length was determined for 368 case subjects and 284 control subjects. Distributions in the two groups were compared by linear and logistic regression, allowing adjustment for measured risk factors. All statistical tests were two-tailed. RESULTS: When analyzed as either a continuous or a dichotomous variable, there was no association between CAG, length and breast cancer risk, before or after adjustment for risk factors. Mean (95% confidence interval [CI]) CAGn lengths were 22.0 (21.8-22.2) for case subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95% CI) of alleles with 22 or more CAGn repeats was 0.531 (0.494-0.568) for case subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment, the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to 0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95% CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal any association. Similar results were obtained when alleles were defined by other cutoff points. CONCLUSION: We found no evidence for an association between AR exon 1 CAGn length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects.
Assuntos
Neoplasias da Mama/metabolismo , Éxons/genética , Receptores Androgênicos/genética , Repetições de Trinucleotídeos/genética , Adulto , Idade de Início , Austrália , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Modelos Lineares , Modelos Logísticos , Razão de Chances , Polimorfismo Genético , Fatores de RiscoRESUMO
Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggests unique mechanisms of molecular pathogenesis: We used a molecular pathological analysis to define the genetic abnormalities relevant to these specific pathogeneses. Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study and stratified by BRCA1 and BRCA2 germline mutation status. Cases were not selected for family history or ethnic origin, and none were known to be genetically related. Thus, germline mutation itself is likely to impact on the molecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BRCA1 mutation carriers had significantly higher levels of p53 expression, including the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable germline mutation. These cancers also had a higher proliferation rate as measured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyclin D1, and estrogen receptor was significantly less common in BRCA1 mutation carriers. Lower levels of cyclin D1 were also found in cancers from BRCA2 mutation carriers compared with non-mutation carriers. Direct p53 mutation analysis revealed mutations in 18% of all of the early-onset breast cancers within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breast cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection for overexpression of several other prognostic factor proteins known to be involved in breast oncogenesis. In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Idade de Início , Proteína BRCA2 , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Feminino , Genética Populacional , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Mutação , Invasividade Neoplásica/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Historically, studies of the "genetic epidemiology" of cancer have used nonsystematically sampled kindreds with numerous cases of cancer across multiple generations. From the epidemiologic viewpoint, it is difficult to extrapolate findings to the population because of the ad hoc ascertainment of these atypical, ill-defined families. Since 1992, we have been conducting a population-based, case-control-family study of breast cancer. METHODS: Families are identified through a single, population-sampled proband, who is either affected or unaffected, making adjustment for ascertainment straightforward. Administered questionnaires and blood samples are sought from cases, controls, and specified sets of relatives. From 1996 through 1999, a further 1200 case families have been recruited as part of the Co-operative Family Registry for Breast Cancer Studies (CFRBCS). Issues relevant to the study design and analysis are discussed. RESULTS: Epidemiologic and genetic findings published to date are summarized. In particular, this population-based study has shown that the so-called "high-risk" families containing multiple cases of breast cancer are not typical of families in the general population in which BRCA1 or BRCA2 mutations are segregating. Most "hereditary" cancers are "sporadic." CONCLUSION: The collection of DNA, as well as data on disease status and risk factors, from population-sampled sets of relatives provides a powerful resource for addressing genetic and environmental determinants of cancer. A population-based multicenter, multidisciplinary enterprise, such as has been developed by the CFRBCS, may become a model for future research in cancer epidemiology, allowing genetic and environmental risk factors to be put into a proper population perspective.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Sistema de Registros , Projetos de Pesquisa , Estudos de Casos e Controles , Família , Feminino , HumanosRESUMO
The average breast cancer risk for carriers of a germ-line mutation in BRCA1 or BRCA2 (penetrance) has been estimated from the multiple-case families collected by the Breast Cancer Linkage Consortium (BCLC) to be approximately 80% to age 70. However, women now being tested for these mutations do not necessarily have the intense family history of the BCLC families. Testing for protein-truncating mutations in exons 2, 11, and 20 of BRCA1 and exons 10 and 11 of BRCA2 was conducted in a population-based sample of 388 Australian women with breast cancer diagnosed before age 40. Onset of breast cancer was analyzed in the known and potential mutation-carrying first- and second-degree female relatives of cases found to carry a mutation. Of the 18 mutation-carrying cases (9 BRCA1 and 9 BRCA2), only 5 (1 BRCA1 and 4 BRCA2) had at least one affected relative, so family history of breast cancer was not a strong predictor of mutation status in this setting. The risk in mutation carriers was, on average, 9 times the population risk [95% confidence interval (CI), 4-23; P < 0.001]. Penetrance to age 70 was 40% (95% CI, 15-65%), about half that estimated from BCLC families. By extrapolation, approximately 6% (95% CI, 2-20%) of breast cancer before age 40 may be caused by protein-truncating mutations in BRCA1 or BRCA2. Breast cancer risk in BRCA1 or BRCA2 mutation carriers may be modified by other genetic or environmental factors. Genetic counselors may need to take into account the family history of the consultand.
Assuntos
Neoplasias da Mama/epidemiologia , Genes Supressores de Tumor/genética , Predisposição Genética para Doença , Mutação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Proteína BRCA2 , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Estudos de Casos e Controles , Primers do DNA , Feminino , Genes BRCA1/genética , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Funções Verossimilhança , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Medição de Risco , Fatores de Transcrição/genéticaRESUMO
The enzyme 5alpha-reductase type II (SRD5A2) converts testosterone to its more active form 5alpha-dihydroxytestosterone. The 3' untranslated region of the gene contains a (TA)(n) length polymorphism. The (TA)(9) allele has been reported to be associated with higher serum prostate-specific antigen levels in breast tumors and lower risk of relapse in breast cancer patients and more recently has also been reported to be linked to the codon 89 valine variant, which is itself associated with higher serum prostate-specific antigen levels in breast tumors and a more favorable breast cancer prognosis. We investigated whether the SRD5A2 (TA)(n) polymorphism was associated with risk of breast or ovarian cancer in Australian women by studying 946 breast cancer cases and 509 age-matched controls, and 544 ovarian cancer cases and 298 controls of similar age distribution. The (TA)(9) allele frequency was similar in breast cancer cases (0.110), breast cancer controls (0.125), ovarian cancer cases (0.106), and ovarian cancer controls (0.117). There was no difference in genotype distribution between breast cancer cases and controls (P = 0.5), ovarian cancer cases and controls (P = 0.7), or between the two control groups (P = 0.9). Genotypes containing at least one (TA)(9) allele were not significantly associated with risk of breast cancer overall (odds ratio, 0.86; 95% confidence interval, 0.67-1.12; P = 0.3) or in women stratified by age, menopausal status, or family history. Similarly, the (TA)(9) allele was not associated with risk of ovarian cancer (odds ratio, 0.87; 95% confidence interval, 0.61-1.23; P = 0.4) or with ovarian tumor behavior (invasive or low malignant potential), histology, stage, or grade. Given that this study had sufficient power to detect altered risks in the order of 1.4- to 1.7-fold, our results suggest that the SRD5A2 (TA)(9) allele is unlikely to be associated with moderate alterations in breast or ovarian cancer risk.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Polimorfismo Genético , Adulto , Fatores Etários , Austrália/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Menopausa , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Fatores de RiscoRESUMO
Population-based women (n=1049) with breast cancer diagnosed mainly between 1996 and 1998, when aged 20-59 years, were mailed a questionnaire seeking information about self-reported shoulder stiffness and swelling, numbness and pain/ache in the arm following treatment (excluding 6 months from diagnosis). Of the 809 who completed the survey, approximately seven in eight experienced at least one symptom, one in six reported all four symptoms, and one in three considered that their arm morbidity interfered substantially with activities of daily living. Arm swelling occurred at some time in 39% of women, was present in 20% 1 year, and in 29% 4 years, after diagnosis. The prevalence of arm swelling was higher in women with axillary node dissection (OR=2.4; 95% Cl 1.0-5.6), and was increased in a women with a higher body mass index (P=0.02) and less education (P=0.01), but was not related to age, number of nodes excised or self-reports of radiation or type of surgery.
RESUMO
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.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Predisposição Genética para Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , MasculinoRESUMO
LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.
Assuntos
Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos/métodos , Judeus/genética , Modelos Estatísticos , Mutação , Adulto , Idoso , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estados UnidosRESUMO
OBJECTIVES: A case-control-family study of breast cancer in women under the age of 40 was carried out in Melbourne and Sydney, Australia, from 1992 to 1995 to determine the risk factors for these women. Subjects included 467 incident cases identified by state cancer registries and 408 population-based controls. METHODS: All participants completed a structured risk-factor questionnaire and family pedigree during an in-person interview. Where possible, cancers in first- and second-degree relatives were verified. RESULTS: Multiple logistic regression analysis showed that the strongest risk factor for breast cancer was a family history of the disease -- having at least one affected first-degree relative trebled the risk (relative risk [RR] = 3.3, 95 percent confidence interval [CI] = 1.9-5.8). Risk increased with height by three percent (standard error [SE] of one percent) per cm, and after adjusting for height, there was evidence for a decreased risk in women weighing 73 kg or more. There was an increased risk of breast cancer after the first full-term birth (RR = 1.8, CI = 1.0-3.5) but this risk fell by 30 percent (SE = 11 percent) with each subsequent livebirth. CONCLUSIONS: The effects of other reproductive factors and oral contraceptive use, although not nominally significant, were in accord with published findings from similar studies in young women. This study of Australian women has indicated that some risk factors for breast cancer in women under age 40 differ from those reported for older women either in direction (e.g., weight) or relative importance (e.g., family history).
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Adulto , Idade de Início , Austrália/epidemiologia , Peso Corporal , Estudos de Casos e Controles , Anticoncepcionais Orais , Feminino , Humanos , Pessoa de Meia-Idade , Paridade , Linhagem , Fatores de RiscoRESUMO
Routinely collected perinatal morbidity data were abstracted for 204 cases of moderate and severe spastic cerebral palsy and 816 matched controls. Separate analyses were conducted for cases with birth-weight > or = 2,500 g and birth-weight < 2,500 g. The presence of a congenital abnormality was an important risk factor for cerebral palsy in both groups and further analyses were conducted after dividing the groups according to presence or absence of a congenital abnormality. In the < 2,500 g group, resuscitation needed was clearly identified as a risk factor for cerebral palsy in the group with no congenital abnormalities (adjusted OR=3.4; 95% CI=1.6-7.5) while in the group with congenital abnormalities, none of the risk factors were clearly associated with an increased risk of cerebral palsy. Among the cases with birth-weight > or = 2,500 g, intrauterine hypoxia/birth asphyxia was clearly associated with an increased risk of cerebral palsy (adjusted OR=18.1; 95% CI=1.8-186) in the group with no congenital abnormalities while in the group with congenital abnormalities, none of the factors were clearly associated with an increased risk of cerebral palsy.
Assuntos
Paralisia Cerebral/epidemiologia , Asfixia Neonatal/epidemiologia , Estudos de Casos e Controles , Causalidade , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple-case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation. METHODS: The study undertook a histologic assessment of breast carcinomas diagnosed before age 40 years identified from a population-based study. RESULTS: Breast carcinoma in BRCA1 mutation carriers was associated with a distinct histologic appearance; these tumors were high grade, and had exceptionally high mean mitotic counts, a syncytial growth pattern, pushing margins, and confluent necrosis. Atypical medullary carcinoma was overrepresented in BRCA1 mutation carriers. All low grade tumors and tumors with low mitotic rates belonged to the group without BRCA1 or BRCA2 mutations. Pleomorphic lobular carcinomas and extensive intraduct carcinomas were more common in BRCA2 mutation carriers. CONCLUSIONS: Breast carcinoma occurring in women with a germline BRCA1 or BRCA2 mutation have recognizable histologic phenotypes, which may be useful in identifying individuals more likely to carry germline mutations. Histologic examination of breast carcinoma should become an important part of the evaluation of women seeking genetic testing for germline mutations in these breast carcinoma susceptibility genes.
Assuntos
Neoplasias da Mama/patologia , Genes BRCA1 , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Vigilância da População , Adulto , Idade de Início , Apoptose , Austrália , Neoplasias da Mama/genética , Feminino , Humanos , Necrose , FenótipoRESUMO
We used data from 765 cases and 564 controls in the population-based Australian Breast Cancer Family Study to investigate whether, in women under the age of 40, the profile of risk factors differed between breast cancer subtypes defined by joint oestrogen and progesterone receptor status. As hypothesised, no significant differences were found.