Gillian S. Dite

The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study.

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.

Breast cancer in Australian women under the age of 40

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).

Oral Contraceptive Use and Risk of Early-Onset Breast Cancer in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations

Background: Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear. Methods: Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls. Results: After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001). Conclusions: There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.

After BRCA1 and BRCA2—What Next? Multifactorial Segregation Analyses of Three-Generation, Population-Based Australian Families Affected by Female Breast Cancer

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years, ascertained through population cancer registries in Melbourne and Sydney, Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes.

BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer

SummaryThe frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-based case–control-family study. Cases were women living in Melbourne or Sydney, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched for age, randomly selected from electoral rolls. Full manual sequencing of the coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a first- or second-degree relative. All detected variants were tested in a random sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast cancer, but did not carry the mutation. The proportion of Australian women with breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% Cl 0.3–12.6%). Seven rare variants were also detected, but for none was there evidence of a strong effect on breast cancer susceptibility. Therefore, on a population basis, rare variants are likely to contribute little to breast cancer incidence.

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.

The Heritability of Mammographically Dense and Nondense Breast Tissue

Background: Percent mammographic density (PMD) is a risk factor for breast cancer. Our previous twin study showed that the heritability of PMD was 63%. This study determined the heritabilities of the components of PMD, the areas of dense and nondense tissue in the mammogram. Methods: We combined two twin studies comprising 571 monozygous and 380 dizygous twin pairs recruited from Australia and North America. Dense and nondense areas were measured using a computer-assisted method, and information about potential determinants was obtained by questionnaire. Under the assumptions of the classic twin model, we estimated the heritability of the log dense area and log nondense area and the genetic and environmental contributions to the covariance between the two traits, using maximum likelihood theory and the statistical package FISHER. Results: After adjusting for measured determinants, for each of the log dense area and the log nondense area, the monozygous correlations were greater than the dizygous correlations. Heritability was estimated to be 65% (95% confidence interval, 60-70%) for dense area and 66% (95% confidence interval, 61-71%) for nondense area. The correlations (SE) between the two adjusted traits were −0.35 (0.023) in the same individual, −0.26 (0.026) across monozygous pairs, and −0.14 (0.034) across dizygous pairs. Conclusion: Genetic factors may play a large role in explaining variation in the mammographic areas of both dense and nondense tissue. About two thirds of the negative correlation between dense and nondense area is explained by the same genetic factors influencing both traits, but in opposite directions. (Cancer Epidemiol Biomarkers Prev 2006;15(4):612–7)

Psychosocial Factors and Survival of Young Women With Breast Cancer: A Population-Based Prospective Cohort Study

PURPOSE Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results. PATIENTS AND METHODS A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors. RESULTS Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008). CONCLUSION The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.

Common genetic variants associated with breast cancer and mammographic density measures that predict disease

Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (P(x)), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P(c)) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (P(u)). For dense area and percent dense area, the distributions of P(c) values were not uniform (both P(u) <0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility.

Monogenic and polygenic determinants of sarcoma risk: an international genetic study

BACKGROUND Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. METHODS In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). FINDINGS The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57-3·14, p=1·2 × 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. INTERPRETATION About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. FUNDING Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.