Julia A. Knight

The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer

IntroductionThe etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia.MethodsThe sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data.ResultsAs of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals.ConclusionThis resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/.

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

IntroductionSeveral common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.MethodsWe evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.ResultsThese analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.ConclusionsThe relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry

Moderate to high‐dose radiotherapy is known to increase the risk of breast cancer. Uncertainties remain about the effects of low‐dose chest X‐rays, particularly in individuals at increased genetic risk. We analyzed case‐control data from the Breast Cancer Family Registry. Self‐reported data on therapeutic and diagnostic radiation exposures to the chest were available for 2,254 breast cancer cases and 3,431 controls (1,556 unaffected sisters and 1,875 unrelated population controls). We used unconditional logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with radiation exposure, after adjusting for age, study center, country of birth, and education. Increased risks for breast cancer were found for women who had radiotherapy for a previous cancer (OR = 3.55, CI = 1.47–8.54) and diagnostic chest X‐rays for tuberculosis (OR = 2.49, CI = 1.82–3.40) or pneumonia (OR = 2.19, CI = 1.38–3.47). Risks were highest for women with a large number of exposures at a young age or exposed in earlier calendar years. There was no evidence of increased risk associated with other diagnostic chest X‐rays (not including tuberculosis or pneumonia), both in women with and without indicators of increased genetic risk (i.e., diagnosed at age <40 years or family history of breast cancer). Given the widespread and increasing use of medical diagnostic radiation, continued surveillance of breast cancer risk is warranted, particularly in women at specific genetic risk, such as those carrying mutations in BRCA1 or BRCA2.

Characteristics Associated with Participation at Various Stages at the Ontario Site of the Cooperative Family Registry for Breast Cancer Studies

PURPOSEnThe Ontario site of the Cooperative Family Registry for Breast Cancer Studies collects cancer family history, other risk factor information, and biospecimens from individuals with incident breast cancer and their relatives within a defined population. Sampling is based on age and defined genetic risk criteria. The purpose of this analysis was to evaluate the representativeness of the respondents.nnnMETHODSnWe examined characteristics associated with response to requests for information, biospecimens, and permission to contact relatives among those diagnosed with breast cancer in 1996 in the province of Ontario.nnnRESULTSnOverall, response was good among the largest group, white women, and did not differ between those with and without a family history of breast and/or ovarian cancer. Women who described themselves as other than white and men tended to have lower response. Women of Ashkenazi heritage had high response except for permission to contact relatives.nnnCONCLUSIONSnThere was no evidence that participation in a familial breast cancer registry derived from a population-based cancer registry was influenced by having a family history of breast or ovarian cancer. The use of a cancer registry approach is likely more representative of the population than clinic-based recruitment of families for genetic studies.

Alcohol metabolism, alcohol intake, and breast cancer risk: a sister-set analysis using the Breast Cancer Family Registry.

Moderate alcohol intake has been consistently associated with a modest (30–50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (nxa0=xa0811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Missense Polymorphisms in the Adenomatous Polyposis Coli Gene and Colorectal Cancer Risk

PurposeWhereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer.MethodsWe sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects.ResultsGermline APC or mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missense APC gene alterations (S130G, E1317Q, D1822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APC Y94X, biallelic MYH Y165C and heterozygous MYH G382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missense APC alterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130Gu2009=u20093.1 (0.29–32.25), E1317Qu2009=u20091.08 (0.59–2.74), G2502Su2009=u20091 (0.65–1.63), D1822V (heterozygous)u2009=u20090.79 (0.64–0.98), D1822V (homozygous)u2009=u20090.82 (0.63–1.27).ConclusionsGermline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.

Accuracy of breast screening among women with and without a family history of breast and/or ovarian cancer

SummaryObjectivesTo compare interval cancer rates, sensitivity and specificity of breast cancer screening between women with moderate or strong family history and women without a family history.MethodsFrom 1996 to 1997, 115,460 women aged 50 to 69 screened by the Ontario Breast Screening Program, offering eligible women screening with mammography and clinical breast examination, were examined. Women were followed for up to 12xa0months after their screening examination. Family history definitions were based on the number of affected first degree relatives and their ages at diagnosis. Multivariate analysis was conducted to adjust for potential confounding variables.ResultsInterval cancer rates increased across family history groups and were greatest in women with a strong family history. The rate ratio (RR) for interval cancer rate in women with a strong family history compared to women without a family history approached significance (RR=2.28, 95% confidence interval (CI) 0.97–5.34), while for women with a moderate family history it did not (RR=1.37, 95% CI 0.62–3.04). A slightly but not significantly lower sensitivity was observed in women with a strong family history compared to women without a family history. There was little variation in specificity across family history groups.ConclusionsScreening was able to detect a large proportion of invasive breast cancers in women with a family history, indicating their potential to benefit from regular breast cancer screening. However, due to increased interval cancer rates, screening with one-year intervals may be important even in an older population of women with a family history.

An inverse association between ovarian cysts and breast cancer in the Breast Cancer Family Registry

Ovarian cysts of several types are common in women of reproductive age. Their etiology is not well understood but is likely related to perturbations in the hypothalamic‐pituitary‐gonadal axis. The relationship of ovarian cysts to breast cancer risk is not known, although a negative association with polycystic ovarian syndrome has been reported. Incident, invasive female breast cancer cases, population‐based controls and unaffected sisters of cases were studied from 3 countries participating in the Breast Cancer Family Registry: Melbourne and Sydney, Australia; the San Francisco Bay Area, USA; and Ontario, Canada. Using the same questionnaire, information was collected on self‐reported history of ovarian cysts and other risk factors. Analyses were based on 3,049 cases, 2,344 population controls and 1,934 sister controls from all sites combined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using both unconditional and conditional logistic regression using an offset term to account for sampling fractions at 2 of the sites. A significantly reduced risk of breast cancer was observed for women reporting a history of ovarian cysts (OR = 0.70, 95% CI 0.59–0.82, among all cases and all controls). This risk estimate was similar regardless of control group used, within all 3 sites and in both premenopausal and postmenopausal women (ORs ranging from 0.68–0.75, all 95% CI excluded 1.00). A self‐reported history of ovarian cysts was strongly and consistently associated with a reduced risk of breast cancer. Further study of ovarian cysts may increase our understanding of hormonal and other mechanisms of breast cancer etiology.

Variation in genes related to obesity, weight and weight change and risk of contralateral breast cancer in the WECARE Study population

Background: Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk. Methods: Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Womens Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression. Results: After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings. Conclusion: Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC. Impact: Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer. Cancer Epidemiol Biomarkers Prev; 21(12); 2261–7. ©2012 AACR.

Ovarian cysts and breast cancer: results from the Women’s Contraceptive and Reproductive Experiences Study

A diagnosis of ovarian cysts is likely an indicator of hormonal milieu and thus may be related to breast cancer risk. Recent studies have reported an inverse relationship between prior ovarian cyst diagnosis and breast cancer risk. We evaluated this relationship in the Women’s Contraceptive and Reproductive Experiences (CARE) Study, a population-based case–control study conducted in Atlanta, Detroit, Philadelphia, Los Angeles, and Seattle. Cases had first primary invasive breast cancer diagnosed between 1994 and 1998 at ages 35–64xa0years. African American women were over-sampled. Controls were identified through random digit dialling and were frequency matched to cases on centre, race, and five-year age group. A total of 4575 cases and 4682 controls were interviewed. We used unconditional logistic regression adjusted for age and study centre within racial groups to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between prior ovarian cysts and breast cancer. Ovarian cyst diagnosis was associated with a significantly reduced risk among Caucasians (ORxa0=xa00.85, 95% CI 0.76–0.96) and among African Americans (ORxa0=xa00.68, 95% CI 0.57–0.81). The association in Caucasians was not significant within subgroups defined by menopausal status, hormone use, or gynecological surgery while the OR estimates in African Americans were consistently lower and frequently significant. These data are consistent with the previously reported inverse association between ovarian cysts and breast cancer, but the evidence for a relationship was stronger in African Americans than Caucasians. Additional studies are required to determine the specific cyst type(s) responsible for the observed relationship.