Theresa Conway

Hereditary breast cancer : pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage

The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1‐related and BRCA2‐related hereditary breast cancer (HBC) and non‐HBC.

Familial breast-ovarian cancer locus on chromosome 17q12-q23

Familial breast cancer has been linked to the D17S74 locus on chromosome 17q. To confirm this finding and to investigate whether ovarian cancer is also linked to this locus, five large families with a hereditary predisposition to cancer of the breast and ovary were investigated. Three families were positive for linkage. For the largest family the lod score was 2.72. These findings suggest that the chromosomal region 17q12-q23, previously shown to contain a gene for early-onset breast cancer, is also associated with a proportion of hereditary ovarian cancers.

A genomewide linkage scan for quantitative-trait loci for obesity phenotypes.

Obesity is an increasingly serious health problem in the world. Body mass index (BMI), percentage fat mass, and body fat mass are important indices of obesity. For a sample of pedigrees that contains >10,000 relative pairs (including 1,249 sib pairs) that are useful for linkage analyses, we performed a whole-genome linkage scan, using 380 microsatellite markers to identify genomic regions that may contain quantitative-trait loci (QTLs) for obesity. Each pedigree was ascertained through a proband who has extremely low bone mass, which translates into a low BMI. A major QTL for BMI was identified on 2q14 near the marker D2S347 with a LOD score of 4.04 in two-point analysis and a maximum LOD score (MLS) of 4.44 in multipoint analysis. The genomic region near 2q14 also achieved an MLS >2.0 for percentage of fat mass and body fat mass. For the putative QTL on 2q14, as much as 28.2% of BMI variation (after adjustment for age and sex) may be attributable to this locus. In addition, several other genomic regions that may contain obesity-related QTLs are suggested. For example, 1p36 near the marker D1S468 may contain a QTL for BMI variation, with a LOD score of 2.75 in two-point analysis and an MLS of 2.09 in multipoint analysis. The genomic regions identified in this and earlier reports are compared for further exploration in extension studies that use larger samples and/or denser markers for confirmation and fine-mapping studies, to eventually identify major functional genes involved in obesity.

Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density

Bone mineral density (BMD) is a major determinant of osteoporotic fractures (OFs). The heritability of BMD ranges from 50% to 90% in human populations. Extensive molecular genetic analyses have been performed through traditional linkage or association approaches to test and identify genes or genomic regions underlying BMD variation. The results, particularly those concerning the vitamin D receptor (VDR) gene, have been inconsistent and controversial. In this study, we simultaneously test linkage and/or association of the genes for VDR, osteocalcin (also known as bone Gla protein [BGP]), and parathyroid hormone (PTH) with BMD in 630 subjects from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with an extreme BMD value at the hip or spine (Z score ≤ −1.28). For the raw BMD values, adjusting for significant covariate effects of age, sex, and weight, we performed tests for linkage alone, association alone, and then both linkage and association. For the spine BMD, at the two markers (ApaI and FokI) inside the VDR gene we found evidence for linkage (p < 0.05) and for both linkage and association by the transmission disequilibrium test (TDT; p < 0.05); association was detected (p < 0.07) with regular statistical testing by analyses of variance (ANOVA). In addition, significant results were found for association alone (p < 0.05), linkage alone (p = 0.0005), and for linkage and association (p = 0.0019) for the intragenic marker HindIII of the BGP gene for the hip BMD. Through testing for association, linkage, and linkage and association simultaneously, our data support the VDR gene as a quantitative trait locus (QTL) underlying spine BMD variation and the BGP gene as a QTL underlying hip BMD variation. However, our data do not support the PTH gene as a QTL underlying hip or spine BMD variation. This is the first study in the broad field of bone genetics that tests candidate genes as QTLs for BMD by testing simultaneously for association alone, for linkage alone, and for association and linkage (via the TDT).

Determination of bone mineral density of the hip and spine in human pedigrees by genetic and life-style factors

In 40 human pedigrees with 563 subjects, we evaluated the contribution of genetic and life‐style factors (exercise, smoking, and alcohol consumption) and the interactions between non‐genetic factors in determining bone mineral density (BMD) of the hip and spine. In our analysis, we adjusted for age, weight, height, menopausal status in females, life‐style factors, and the significant interactions among these factors. For the spine and hip BMD, heritabilities (h2) (± SE) were, respectively, 0.68 (0.21) and 0.86 (0.28) in males and 0.64 (0.13) and 0.67 (0.14) in females. Exercise had significant beneficial effects for male spine BMD and female hip BMD. Alcohol consumption experienced in our sample had significant beneficial effects on hip BMD in both sexes. Although the main effect of smoking was not significant, there were significant interaction effects between smoking and other important factors (e.g., exercise, weight, alcohol consumption). For example, for female spine BMD, exercise had significant beneficial effects in smokers; however, its effect in non‐smokers was non‐significant. This result indicates that exercise may reduce deleterious effects of smoking (if any) on BMD, but may have minor effects in increasing BMD in non‐smokers. The various interaction effects among risk factors explicitly revealed here for the first time indicate that the detailed effects and direction of individual risk factors may depend on the presence and magnitude of other factors. Weight invariably affected BMD of the hip and spine in both sexes. Age effects were significant for hip BMD, but not for male spine BMD. Genet. Epidemiol. 19:160–177, 2000.

Hereditary ovarian cancer. Heterogeneity in age at diagnosis

An unknown fraction of the ovarian cancer burden occurs in women with a family history indicative of a putative autosomal dominantly inherited cancer susceptibility syndrome. The results from a five‐generation, extended, hereditary breast‐ovarian cancer kindred are described 10 years after it was initially ascertained. Significantly more cancers were observed in high‐risk family members during this decade than were expected (P < 0.001). The age of ovarian cancer diagnosis was studied in additional ovarian cancer‐prone families of three types: site‐specific ovarian cancer syndrome, the breast–ovarian cancer syndrome, and Lynch syndrome II. The age of onset in each of the three sets was significantly (P < 0.001) earlier than the general population mean of 59, and there were significant differences in the age of onset (P = 0.050) among these three cohorts. Ovarian cancer histology was similar to that of patients with negative family histories. There may be clinically significant heterogeneity in the age at diagnosis of ovarian cancer among these ovarian cancer‐prone syndromes. This has important implications for understanding its natural history and targeting surveillance–management strategies.

Breast Cancer Family History as a Risk Factor for Early Onset Breast Cancer

SummarySince full breast cancer screening is not generally recommended for young women, it is important to identify individuals who are at higher risk for early onset breast cancer. We investigated the relationship between age of onset of breast cancer in 328 probands (consecutively ascertained patients from our oncology clinic) and breast cancer incidence and age of onset in their female relatives. We found that a family history of early onset breast cancer was associated with higher risk of early onset breast cancer. A family history of early onset breast cancer occurred more frequently among young (<40) breast cancer probands than among older (⩾40) breast cancer probands (p<0.001; OR = 23). This relationship was particularly evident when the analysis was restricted to thehereditary breast cancer probands (p<0.001; OR = 44). We also observed a positive family history of breast cancer (any age) more frequently in young breast cancer probands than in older breast cancer probands (p<0.001; OR = 2.8). These observations have important pragmatic implications for surveillance. We recommend intense surveillance for breast cancer, initiated earlier, for women with close relatives diagnosed with early onset breast cancer.

A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and Xq27

Background: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation. Objective: To substantiate these previous findings and detect new genomic regions. Methods: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced ∼8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method. Results: The strongest linkage signal was obtained on Xq27 with two point LOD scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in two earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12. Conclusions: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.

Genetic Determination of Variation and Covariation of Peak Bone Mass at the Hip and Spine

The likelihood of low trauma fracture in the elderly is highly predictable by peak bone mass (PBM) at age approximately 25-50 yr. We estimated the magnitude of genetic determination of the variation and covariation of PBM of the spine and hip (adjusted by age, gender, and ethnicity) in 47 independent healthy full-sib pairs and 27 healthy mother-offspring pairs. For the spine and hip, the narrow-sense heritabilities (h(2)) (mean +/- SE) were 0.76 +/- 0.34 and 0.84 +/- 0.36, respectively, when estimated from full sibs, and 0.86 +/- 0.38 and 0.84 +/- 0.39, respectively, when estimated from parent-offspring. Some genetic loci underlying PBM variation at the hip and spine are the same or closely linked, as is reflected by the high genetic correlation of 0.95 +/- 0.05 between them when estimated from full sibs, and 0.57 +/- 0.27 when estimated from parent-offspring, respectively. Generally, common familial environmental effects shared by relatives may bias these estimates. However, these effects may be small, since our results reported herein and those in other earlier studies indicate that common familial environmental effects are probably negligible in causing similarity of bone mass among family members. The correlation of bone mass among randomly sampled couples living in the same household is small and nonsignificant as measured either by densitometry at the radius and ulna or by quantitative ultrasound at the patella. The problem of shared environmental effects notwithstanding, we conclude that much of the PBM variation and covariation at the hip and spine is determined genetically.

Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density.

Bone mineral content (BMC) and/or bone mineral density (BMD, i.e. BMC scaled by bone size) are major determinants for osteoporosis, which is a serious health problem. The major determinant of variation in BMD/BMC is genetic. The few studies now available are inconsistent in the identification and/or even in the existence of major gene(s) for BMD/BMC. In 51 human pedigrees with 941 individuals (526 measured for phenotypes) identified via probands with extreme BMD values, we performed complex segregation analyses to test the existence of a genetic locus with a major effect on BMD/BMC variation. We analyzed BMD and BMC at the spine, hip and wrist jointly by employing, as the study phenotype, factor scores (FS) of the principle component that explains ∼75% of the total BMD/BMC variation at the three sites. The results indicate that a major gene exists with a codominant effect that is responsible for ∼16% of the FS variation when adjusted for significant effects of sex, body weight and age. A significant genotype‐×‐sex‐×‐age interaction was found, which may explain ∼14% of the FS variation after adjusting for body weight. Testing of various models did not provide support for shared familial environmental effects but suggested the existence of residual polygenic effects, which may explain ∼50% of the FS variation when adjusting for sex, body weight and age. This study indicates a promising aspect of studies to identify a major gene for BMD/BMC variation in our pedigrees identified via extreme probands.