Claire N. Singletary

Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian

Previous studies have reported additional cancers associated with BRCA mutations; however, the type, magnitude of risk, and sex differences remain to be clarified. The purpose of this study was to evaluate the incidence of cancers other than breast and ovarian cancer in known mutation carriers.

NSGC practice guideline: Prenatal screening and diagnostic testing options for chromosome aneuploidy

The BUN and FASTER studies, two prospective multicenter trials in the United States, validated the accuracy and detection rates of first and second trimester screening previously reported abroad. These studies, coupled with the 2007 release of the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin that endorsed first trimester screening as an alternative to traditional second trimester multiple marker screening, led to an explosion of screening options available to pregnant women. ACOG also recommended that invasive diagnostic testing for chromosome aneuploidy be made available to all women regardless of maternal age. More recently, another option known as Non-invasive Prenatal Testing (NIPT) became available to screen for chromosome aneuploidy. While screening and testing options may be limited due to a variety of factors, healthcare providers need to be aware of the options in their area in order to provide their patients with accurate and reliable information. If not presented clearly, patients may feel overwhelmed at the number of choices available. The following guideline includes recommendations for healthcare providers regarding which screening or diagnostic test should be offered based on availability, insurance coverage, and timing of a patient’s entry into prenatal care, as well as a triage assessment so that a general process can be adapted to unique situations.

The impact of noninvasive prenatal testing on the practice of maternal-fetal medicine

OBJECTIVE Noninvasive prenatal testing (NIPT) via cell-free fetal DNA in the maternal circulation is a highly sensitive and specific new testing option. The objective of this study was to determine the impact of NIPT on the uptake of first trimester screening (FTS) and invasive genetic testing. STUDY DESIGN Uptake of prenatal testing was investigated in women referred for advanced maternal age or abnormal screening to the University of Texas Health Maternal-Fetal Medicine Clinics in Houston. Patients who presented from August to November 2011, before clinical introduction of NIPT, were compared with patients who presented from March to June 2012, after its introduction. RESULTS In patients referred between 14 and 22 weeks gestational age, invasive genetic testing was significantly reduced following the introduction of NIPT (35.4 vs. 17.9%, p < 0.05). For patients referred at < 14 weeks gestational age, FTS was significantly reduced with NIPT introduction (89.1 vs. 59.1%, p < 0.05); however, invasive genetic testing was not significantly different (20.0 vs. 14.0%, p > 0.05). CONCLUSION NIPT has made an impact on the practice of maternal-fetal medicine by significantly decreasing the number of second trimester diagnostic tests performed. In addition, patients interested in early screening information appear to prefer the higher sensitivity and specificity of NIPT.

2013 Review and Update of the Genetic Counseling Practice Based Competencies by a Task Force of the Accreditation Council for Genetic Counseling.

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors’ roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force’s work, key changes and the 2013 PBCs are presented herein.

Cancer Incidence in First- and Second-Degree Relatives of BRCA1 and BRCA2 Mutation Carriers

BACKGROUND Mutations in the BRCA1 and BRCA2 genes are associated with increased risk of breast, ovarian, and several other cancers. The purpose of the present study was to evaluate the incidence of cancer in first- and second-degree relatives of BRCA mutation carriers compared with the general population. MATERIALS AND METHODS A total of 1,086 pedigrees of BRCA mutation carriers was obtained from a prospectively maintained, internal review board-approved study of persons referred for clinical genetic counseling at the University of Texas MD Anderson Cancer Center. We identified 9,032 first- and second-degree relatives from 784 pedigrees that had demonstrated a clear indication of parental origin of mutation. Standardized incidence ratios (SIRs) were used to compare the observed incidence of 20 primary cancer sites to the expected incidence of each cancer based on the calculated risk estimates according to each subjects age, sex, and ethnicity. RESULTS BRCA1 families had increased SIRs for breast and ovarian cancer (p < .001) and decreased SIRs for kidney, lung, prostate, and thyroid cancer and non-Hodgkins lymphoma (p < .001). BRCA2 families had increased SIRs for breast, ovarian, and pancreatic cancer (p < .001) and decreased SIRs for kidney, lung, thyroid, and uterine cancer and non-Hodgkins lymphoma (p < .0025). Analysis of only first-degree relatives (n = 4,099) identified no decreased SIRs and agreed with the increased SIRs observed in the overall study population. CONCLUSION We have confirmed previous reports of an association between breast, ovarian, and pancreatic cancers with BRCA mutations. Additional research to quantify the relative risks of these cancers for BRCA mutation carriers can help tailor recommendations for risk reduction and enhance genetic counseling. IMPLICATIONS FOR PRACTICE BRCA gene mutations have been well described to carry an increased risk of both breast and ovarian cancer. However, the implications and risks of other cancers continues to be investigated. Evaluating the risks for other cancers further is key in identifying and managing risk reduction strategies.

Erratum: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian (Cancer. 2015;121 (269-275))

Bladder BRCA1 0 1.282 0 0-2.862 .554 BRCA2 1 1.373 0.728 0.010-4.053 .791 Brain and CNS BRCA1 3 1.268 2.367 0.849-8.078 .269 BRCA2 1 1.077 0.929 0.012-5.168 .578 Breast, female BRCA1 345 9.349 36.902 33.110-41.009 <.001a BRCA2 246 8.885 27.688 24.336-31.373 <.001a Cervical BRCA1 2 1.701 1.176 0.132-4.245 .990 BRCA2 6 1.361 4.410 1.61-9.599 .006 Colorectal BRCA1 6 3.800 1.579 0.577-3.437 .367 BRCA2 2 3.783 0.529 0.059-1.909 .542 Esophagus BRCA1 1 0.405 2.471 0.032-13.75 .654 BRCA2 0 0.422 0 0-8.694 .677 Hodgkin lymphoma BRCA1 3 0.792 3.788 0.761-11.067 .095 BRCA2 0 0.634 0 0-5.787 .929 Non-Hodgkin lymphoma BRCA1 0 2.114 0 0-1.735 .237 BRCA2 1 1.980 0.505 0.007-2.81 .825 Kidney BRCA1 2 1.806 1.107 0.124-3.998 .925 BRCA2 3 1.735 1.729 0.348-5.052 .500 Leukemia BRCA1 5 1.694 2.951 0.951-6.887 .060 BRCA2 3 1.493 2.010 0.404-5.872 .376 Lung BRCA1 2 4.547 0.440 0.049-1.588 .335 BRCA2 5 4.867 1.027 0.331-2.398 .929 Myeloma BRCA1 1 0.462 2.164 0.028-12.04 .728 BRCA2 0 0.477 0 0-7.683 .747 Oral cavity BRCA1 2 1.362 1.468 0.165-5.30 .784 BRCA2 1 1.298 0.770 0.01-4.286 .739 Ovarian BRCA1 178 1.280 139.115 119.427-161.122 <.001 BRCA2 87 1.1614 74.926 60.011-92.422 <.001

Developing a Model of Advanced Training to Promote Career Advancement for Certified Genetic Counselors: An Investigation of Expanded Skills, Advanced Training Paths, and Professional Opportunities

There are currently multiple paths through which genetic counselors can acquire advanced knowledge and skills. However, outside of continuing education opportunities, there are few formal training programs designed specifically for the advanced training of genetic counselors. In the genetic counseling profession, there is currently considerable debate about the paths that should be available to attain advanced skills, as well as the skills that might be needed for practice in the future. The Association of Genetic Counseling Program Directors (AGCPD) convened a national committee, the Committee on Advanced Training for Certified Genetic Counselors (CATCGC), to investigate varied paths to post-master’s training and career development. The committee began its work by developing three related grids that view career advancement from the viewpoints of the skills needed to advance (skills), ways to obtain these skills (paths), and existing genetic counselor positions that offer career change or advancement (positions). Here we describe previous work related to genetic counselor career advancement, the charge of the CATCGC, our preliminary work in developing a model through which to view genetic counselor advanced training and career advancement opportunities, and our next steps in further developing and disseminating the model.

Patient Perception of Negative Noninvasive Prenatal Testing Results.

Objective To determine patient perception of residual risk after receiving a negative non-invasive prenatal testing result. Introduction Recent technological advances have yielded a new method of prenatal screening, non-invasive prenatal testing (NIPT), which uses cell-free fetal DNA from the mothers blood to assess for aneuploidy. NIPT has much higher detection rates and positive predictive values than previous methods however, NIPT is not diagnostic. Past studies have demonstrated that patients may underestimate the limitations of prenatal screening; however, patient perception of NIPT has not yet been assessed. Methods and Materials We conducted a prospective cohort study to assess patient understanding of the residual risk for aneuploidy after receiving a negative NIPT result. Ninety-four participants who had prenatal genetic counseling and a subsequent negative NIPT were surveyed. Results There was a significant decline in general level of worry after a negative NIPT result (p = <0.0001). The majority of participants (61%) understood the residual risk post NIPT. Individuals with at least four years of college education were more likely to understand that NIPT does not eliminate the chance of trisomy 13/18 (p = 0.012) and sex chromosome abnormality (p = 0.039), and were more likely to understand which conditions NIPT tests for (p = 0.021), compared to those women with less formal education. Conclusion These data demonstrate that despite the relatively recent implementation of NIPT into obstetric practice, the majority of women are aware of its limitations after receiving genetic counseling. However, clinicians may need to consider alternative ways to communicate the limitations of NIPT to those women with less formal education to ensure understanding.

BRCAPRO 6.0 Model Validation in Male Patients Presenting for BRCA Testing

BACKGROUND BRCAPRO is a risk assessment model to estimate the risk of carrying a BRCA mutation. BRCA mutation carriers are at higher risk of developing breast, ovarian, pancreatic, and prostate cancer. BRCAPRO was developed for women and found to be superior to other risk assessment models. The present study evaluated the validity of BRCAPRO at predicting the risk of male patients carrying a BRCA mutation. PATIENTS AND METHODS A total of 146 men who presented for genetic counseling and testing from February1997 to September 2011, and their test results were included in the present study. BRCAPRO risk assessment for all patients was calculated using the BRCAPRO clinical CancerGene assessment software. RESULTS The mean age at presentation was 57 years. Of the 146 patients, 48 had breast cancer, 18 had pancreatic cancer, 39 had prostate cancer, 27 had other primary cancers, and 37 had no cancer. Fifty patients (34%) tested positive for a BRCA mutation (22 BRCA1, 27 BRCA2, and 1 BRCA1 and BRCA2). The mean BRCAPRO score for all patients was 24.96%. The BRCAPRO score was significantly higher for patients who tested positive for a BRCA mutation (46.19% vs. 13.9%, p < .01). The area under the receiver operating characteristics curve was 0.83 for all patients for the BRCAPRO score to predict the risk of carrying a BRCA mutation. At a cutoff point of 30.02%, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.74, 0.81, 0.67, and 0.86, respectively. CONCLUSION BRCAPRO appears to be a valid risk assessment tool for determining the risk of carrying a BRCA mutation in men. IMPLICATIONS FOR PRACTICE Men carrying genetic mutations in the BRCA gene have a greater risk than the general population of developing certain types of cancer, including breast, pancreatic, and prostate cancer. BRCAPRO is a risk assessment model that predicts the risk of carrying a BRCA mutation. The present study aimed at validating BRCAPRO for use with men seen for genetic counseling, whether affected by cancer or not. The data available for 146 patients revealed that BRCAPRO was effective at identifying patients at risk of BRCA mutation. These findings could help in identifying a subset of high-risk patients who should proceed to genetic testing.

Prenatal chromosomal microarray uptake with invasive prenatal diagnosis: How many patients take the leap?

Characterize the uptake of chromosomal microarray analysis (CMA) among women undergoing invasive prenatal diagnosis at a large academic institution over a 4‐year time period.