Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond.

Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of women's health.

Genetic counselors' (GC) knowledge, awareness, understanding of clinical next-generation sequencing (NGS) genomic testing.

Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next-generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer-related counseling, exposure to NGS testing, and NGS-focused education. Substantial disagreement about the role of counseling for tumor-based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation.

Oral contraceptive and reproductive risk factors for ovarian cancer within sisters in the breast cancer family registry.

BACKGROUND: Oral contraceptive use has been consistently associated with a reduced risk of ovarian cancer in unrelated, average risk women; however little data exist on whether this benefit extends to higher risk women from cancer families. To examine this, we conducted family-based analyses using the Breast Cancer Family Registry. METHODS: We used generalised estimating equations to obtain the population average effect across all families (n=389 cases, n=5643 controls) and conditional logistic regression to examine within-family differences in a subset with at least two sisters discordant on ovarian cancer status (n=109 cases, n=149 unaffected sister controls). RESULTS: In the multivariable generalised estimating equation model there was a reduced risk of ovarian cancer for ever use of oral contraceptives compared with never use (OR=0.58, 95% CI: 0.37, 0.91), and in the conditional logistic model there was a similar inverse association; however, it was not statistically significant (OR=0.52, 95% CI: 0.23, 1.17). We examined this association by BRCA1/2 status and observed a statistically significant reduced risk in the non-carriers only. CONCLUSION: We observed a decreased risk of ovarian cancer with oral contraceptive use supporting that this association observed in unrelated women extends to related women at higher risk.

Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results.

BRCA1/2 test disclosure has, historically, been conducted in-person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased. Semi-structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions. One hundred and ninety-four genetic counselors completed self-administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre-test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty-two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p < 0.01) than other results. Overall, 73% of participants reported interest in telephone disclosure. Many genetic counselors have provided telephone disclosure, however, most, infrequently. Genetic counselors identify potential advantages and disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted.

Measuring, and identifying predictors of women's perceptions of three types of breast cancer risk: population risk, absolute risk and comparative risk.

Although a key function of cancer genetics services is to provide risk information, to date there has been little consistency in the way in which breast cancer risk perception has been measured. The aims of the study were to measure estimates of (i) population risk, (ii) absolute risk and (iii) comparative risk of developing breast cancer for Ashkenazi Jewish women, and to determine predictors of breast cancer risk perception. Of 152 women, 107 (70%) completed all questions. The mean (s.d.) estimates for population risk, absolute risk and comparative risk were 22.7% (15.9), 31.8% (20.6) and 1.9-fold (1.9), respectively. Most women overestimated population risk. Women at population risk generally overestimated the population risk and their own absolute risk, yet understood they are at the same risk as the population. Those with a family history understood that they are at increased risk, but underestimated the extent to which their familial risk is increased. Anxiety, high estimation of population risk and lesser family history predicted overestimation of absolute risk, whereas high estimation of population risk and a strong family history predicted underestimation of comparative risk.

Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women.

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.

A discrete choice experiment of preferences for genetic counselling among Jewish women seeking cancer genetics services.

To determine which aspects of breast cancer genetic counselling are important to Ashkenazi Jewish women, a discrete choice experiment was conducted. Participants consisted of 339 Australian Ashkenazi Jewish women who provided a blood sample for research used to test for Ashkenazi Jewish ancestral mutations in the genes BRCA1 and BRCA2, and were offered their genetic test result through a cancer genetics service. Main outcome measures were women's preferences for, and trade-offs between, the genetic counselling aspects of providing cancer, gene, and risk information (information); giving advice about cancer surveillance (surveillance); preparing for genetic testing (preparation); and, assistance with decision-making (direction). Respondents most valued information, about twice as much as advice about surveillance, four times as much as preparation for testing, and nine times as much as assistance with decision-making, which was least valued. Women's preferences were consistent with the major goals of genetic counselling, which include providing information and surveillance advice, and avoiding direction by facilitating autonomous decision-making. There were differences between the women in which aspects they most favoured, suggesting that counselling that elicits and responds to clients' preferences is more likely to meet clients' needs.

Communicating genetic test results to the family: a six-step, skills-building strategy.

As the availability of tests to identify hereditary predisposition to chronic diseases continues to grow, a need has arisen to prepare individuals receiving genetic test results to share this highly sophisticated and value-laden information with other at-risk family members. Responding to this need, a communication skills-building intervention, based on Buckman's model of "Breaking Bad News," was developed for use in the setting of genetic testing for BRCA1 and BRCA2 mutations. Outcomes will include knowledge, attitudes, and health behavior on the part of both the proband and her first-degree relatives.

Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history.

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.

Anxiety/uncertainty reduction as a motivation for interest in prophylactic oophorectomy in women with a family history of ovarian cancer.

Most women at familial risk for ovarian cancer must decide about prophylactic oophorectomy without conclusive genotypic information about their risk level. Some women with relatively low-risk profiles seek prophylactic oophorectomy or are recommended the procedure by their physicians, if they appear "cancerphobic." This study investigated the desire to reduce anxiety in relation to other factors associated with interest in prophylactic oophorectomy in a group of women with varying degrees of familial risk for ovarian cancer. Ninety-four women enrolled in an ongoing program for women with a family history of ovarian cancer received personalized risk counseling and were classified as having a sporadic, familial, or putative hereditary pedigree by a genetics counselor. Eligible enrollees were interviewed by telephone about current and future interest in prophylactic oophorectomy, perceived risk of ovarian cancer, severity of cancer anxiety, stress-related ideation, and reasons for and against surgery. Reduction of anxiety/uncertainty was the factor most strongly associated with current interest in prophylactic oophorectomy, independent of objective risk classification, perceived risk, severity of cancer anxiety, intrusive ideation, or other variables. Future interest in prophylactic oophorectomy was predicted by other perceived benefits of surgery. Current, but not future, interest in prophylactic oophorectomy appears motivated in part by seeking immediate relief from anxiety. Interest in prophylactic oophorectomy may fluctuate based on varying exposure to cues that trigger anxiety. Women seeking prophylactic oophorectomy, particularly those with lower-risk family pedigrees, should be offered options for anxiety management as part of informed consent for prophylactic oophorectomy.

Quantitative studies of the vasculature of the carotid body in the chronically hypoxic rat.

The carotid bodies of rats made chronically hypoxic by breathing 12% O2 in a normobaric chamber (inspired PO2 91 mmHg) were compared with those of controls. Serial 5-microm sections of the organs were examined using an interactive image analysis system. The total volume of the carotid bodies was increased by 64%. The total vascular volume rose by 103% and was likely due to an increase in size of the large vessels (>12 microm lumen diameter) because the small vessel (5-12 microm lumen diameter) volume did not increase significantly while the small vessel density tended to decrease. The extravascular volume was increased by 57%. Expressed as a percentage of the total volume of the organ, the total vascular volume did not change, but the small vessel volume was significantly decreased from 7.83 to 6.06%. The large vessel volume must therefore have been increased. The proportion occupied by the extravascular volume was virtually unchanged (84 vs 82%). In accordance with these findings, the small vessel endothelial surface area per unit carotid body volume was diminished from 95.2 to 76.5 mm-1, while the extravascular area per small vessel was increased from 493 to 641 microm(2) or by 30%. In conclusion, the enlargement of the carotid body in chronic hypoxia is most likely due to an increase in total vascular volume, mainly involving the "large" vessels, and to an increase in extravascular volume. This is in contrast to our previously published findings indicating that in the spontaneous insulin-dependent diabetic rat the enlargement of the carotid body is due solely to an increase in extravascular volume.

Decision making about prophylactic oophorectomy among at-risk women: psychological influences and implications.

OBJECTIVE: Women with a family history of ovarian cancer are confronted with difficult decisions regarding the management of their risk status. Currently, the main preventive option available is prophylactic oophorectomy. The objective of the present paper is to review research and theory on psychological factors that influence decision making about preventive surgery and discuss the implications for patient management. METHODS: Guided by a cognitive-social framework, the literature on decision making about preventive surgery is reviewed and integrated. RESULTS: The available studies show that women are more likely to opt for surgery if they feel more vulnerable to cancer, believe that surgery will prevent cancer, and are worried about developing cancer. Further, the response to ovarian risk is influenced by the individual's characteristic psychological style: monitors (who typically scan for and amplify threatening cues) tend to feel more vulnerable to cancer and more distressed about their cancer risk than blunters (who typically distract from threatening cues) do. CONCLUSION: On the basis of prior research, monitors may be more likely to choose surgical intervention to reduce their distress, without fully anticipating the psychological and medical consequences of that decision. In order to facilitate informed decision making, counseling protocols should be designed to enable the patient to understand and take account of the psychological consequences of the available medical options. Future studies are needed to systematically extend and explore the proposed theory-based relationships.

Specific worry about breast cancer predicts mammography use in women at risk for breast and ovarian cancer.

This longitudinal study examined predictors of mammography use among women with a family history of breast cancer participating in a risk assessment and surveillance program (N = 213). Assessed were background variables (age, prior mammography utilization), cognitive variables (perceived vulnerability), and affective variables (cancer worry and general distress). Results of logistic regression analyses predicting adherence 1 year after baseline contact, in which variables of prior utilization, feelings of vulnerability, and general distress were controlled for, indicated that cancer worry and age were significant predictors of mammography adherence. Results suggest that moderate levels of cancer worry facilitate, rather than undermine, adherence. The results have implications for the construction of educational messages that should be designed to acknowledge feelings of cancer-specific worry and to provide guidance in health protective behaviors.

Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.

Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

The central action of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on cardiac inotropy and vascular resistance in the anaesthetized cat.

Experiments were carried out to determine the effects of the application of the selective 5-HT2 receptor agonist DOI intravenously (in the presence of the peripherally acting 5-HT2 receptor antagonist, BW501C67, 1 mg kg(-1), i.v.) or to the 'glycine sensitive area' of the ventral surface (30 microg each side) on the left ventricular inotropic (left ventricular dP/dt max) and vascularly isolated hindlimb responses in anaesthetized cats. For the ventral surface experiments, NMDA (10 microg each side) was applied to act as a positive control. In all experiments heart rate and mean arterial blood pressure were held constant to exclude any secondary effects caused by changes in these variables. DOI (n=6) i.v or on the ventral surface had no effect on left ventricular dP/dt max but caused a significant increase in hindlimb perfusion pressure of 40+/-9 and 50+/-14 mmHg, respectively. Respiration was unaffected. NMDA (n=6), applied to the ventral surface, caused significant increases in both left ventricular dP/dt max and hindlimb perfusion pressure of 1,950+/-349 mmHg s(-1) and 69+/-17 mmHg respectively, with no associated change in left ventricular end-diastolic pressure. The amplitude of respiratory movements increased. It is concluded that activation of 5-HT2 receptors at the level of the rostral ventrolateral medulla (RVLM) excites sympathetic premotor neurons and/or their antecedents controlling hindlimb vascular resistance but not those controlling the inotropic effects on the left ventricle.

Is hereditary site-specific ovarian cancer a distinct genetic condition?

It is not clear if hereditary site-specific ovarian cancer exists as a genetic entity distinct from the hereditary breast-ovarian cancer syndrome. We have identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. Initially, linkage analysis for this kindred generated a negative LOD score to BRCA1, but subsequent mutation and haplotype analysis of key individuals demonstrated a BRCA1 185delAG mutation segregating with all but 1 of the ovarian cancer cases. This observation has important implications for genetic counselling of families with site-specific ovarian cancer. Hereditary site-specific ovarian cancer is likely to be a variant of the hereditary breast-ovarian cancer syndrome, attributable to either BRCA1 or BRCA2. We consider women from these families to be at increased risk of breast cancer and counsel them accordingly.