Kristen J. Vogel

BRCA1 and BRCA2 Genetic Testing in Hispanic Patients: Mutation Prevalence and Evaluation of the BRCAPRO Risk Assessment Model

PURPOSE The BRCAPRO model, used to predict a familys likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics. PATIENTS AND METHODS A descriptive analysis of mutation frequency and spectrum was performed for Hispanic patients who underwent BRCA1 and BRCA2 genetic testing at a single institution. For comparative analysis of the BRCAPRO risk model, Hispanic patients who underwent comprehensive analysis were compared with white controls using area under the receiver operating characteristic curves (AUROC). RESULTS Fourteen Hispanic individuals who underwent comprehensive analysis were identified to carry a mutation in BRCA1 or BRCA2 (17.9%; 95% CI, 10.2% to 28.3%) and seven individuals had a variant of uncertain significance (9.0%; 95% CI, 12.0% to 30.8%). A total of eight different mutations and three variants were observed within the entire Hispanic population. When evaluating the performance of the BRCAPRO model, the AUROC for Hispanics was 0.774 (95% CI, 0.63 to 0.90), compared with the AUROC of 0.770 (95% CI, 0.65 to 0.89) for whites. CONCLUSION Deleterious BRCA1 and BRCA2 mutations occur at considerable frequency within the Hispanic population, many of which have been identified previously in other ethnic populations. The BRCAPRO model appears to perform equally well in Hispanics as in whites.

The Evolution of Cancer Risk Assessment in the Era of Next Generation Sequencing

Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address.

Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: A multicenter study

OBJECTIVES:The objective of this study was to examine the association between tobacco and alcohol dose and type and the age of onset of pancreatic adenocarcinoma (PancCa).METHODS:Prospective data from the Pancreatic Cancer Collaborative Registry were used to examine the association between age of onset and variables of interest including: gender, race, birth country, educational status, family history of PancCa, diabetes status, and tobacco and alcohol use. Statistical analysis included logistic and linear regression, Cox proportional hazard regression, and time-to-event analysis.RESULTS:The median age to diagnosis for PancCa was 66.3 years (95% confidence intervals (CIs), 64.5–68.0). Males were more likely than females to be smokers (77% vs. 69%, P=0.0002) and heavy alcohol and beer consumers (19% vs. 6%, 34% vs. 19%, P<0.0001). In univariate analysis for effects on PancCa presentation age, the following were significant: gender, alcohol and tobacco use (amount, status and type), family history of PancCa, and body mass index. Both alcohol and tobacco had dose-dependent effects. In multivariate analysis, alcohol status and dose were independently associated with increased risk for earlier PancCa onset with greatest risk occurring in heavy drinkers (HR 1.62, 95% CI 1.04–2.54). Smoking status had the highest risk for earlier onset pancreatic cancer with a HR of 2.69 (95% CI, 1.97–3.68) for active smokers and independent effects for dose (P=0.019). The deleterious effects for alcohol and tobacco appear to resolve after 10 years of abstinence.CONCLUSIONS:Alcohol and tobacco use are associated with a dose-related increased risk for earlier age of onset of PancCa. Although beer drinkers develop pancreatic cancer at an earlier age than nondrinkers, alcohol type did not have a significant effect after controlling for alcohol dose.

Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1

BACKGROUND AND OBJECTIVES The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation). RESULTS Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. CONCLUSION MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome

Objective: Li–Fraumeni syndrome (LFS) confers an increased risk of multiple types of cancer in both children and adults. Clinical genetic testing for deleterious germline p53 gene mutations can identify most LFS‐affected families. We evaluated factors associated with cancer‐specific distress and perceived self‐efficacy in coping with a positive genetic test result among persons at risk of having deleterious p53 mutations.

High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers

Mutations in BRCA1 and BRCA2 increase a womans lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis. We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers. Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively. Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.

Susceptibility to Breast Cancer: Hereditary Syndromes and Low Penetrance Genes

Several genes are associated with hereditary susceptibility to breast cancer. Most notably these include BRCA1 and BRCA2; however, other less common gene mutations which confer elevated breast cancer risk are associated with Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, ataxia-telangiectasia heterozygosity and hereditary diffuse gastric cancer. In this article we highlight the genetic epidemiology, gene function, genotype-phenotype correlations, cancer risks and clinicopathologic findings for the cancer susceptibility genes related to these syndromes. We also examine genes, such as CHEK2, which confer a lower penetrance for breast cancer in comparison to these highly penetrant genes.

10 rare tumors that warrant a genetics referral.

The number of described cancer susceptibility syndromes continues to grow, as does our knowledge on how to manage these syndromes with the aim of early detection and cancer prevention. Oncologists now have greater responsibility to recognize patterns of cancer that warrant referral for a genetics consultation. While some patterns of common cancers are easy to recognize as related to hereditary cancer syndromes, there are a number of rare tumors that are highly associated with cancer syndromes yet are often overlooked given their infrequency. We present a review of ten rare tumors that are strongly associated with hereditary cancer predisposition syndromes: adrenocortical carcinoma, carcinoid tumors, diffuse gastric cancer, fallopian tube/primary peritoneal cancer, leiomyosarcoma, medullary thyroid cancer, paraganglioma/pheochromocytoma, renal cell carcinoma of chromophobe, hybrid oncocytoic, or oncocytoma histology, sebaceous carcinoma, and sex cord tumors with annular tubules. This review will serve as a guide for oncologists to assist in the recognition of rare tumors that warrant referral for a genetic consultation.

Using a Family History Intervention to Improve Cancer Risk Perception in a Black Community

Few studies examine the use of family history to influence risk perceptions in the African American population. This study examined the influence of a family health history (FHH) intervention on risk perceptions for breast (BRCA), colon (CRC), and prostate cancers (PRCA) among African Americans in Pittsburgh, PA. Participants (n = 665) completed pre- and post-surveys and FHHs. We compared their objective and perceived risks, classified as average, moderate, or high, and examined the accuracy of risk perceptions before and after the FHH intervention. The majority of participants had accurate risk perceptions post-FHH. Of those participants who were inaccurate pre-FHH, 43.3%, 43.8%, and 34.5% for BRCA, CRC, and PRCA, respectively, adopted accurate risk perceptions post-FHH intervention. The intervention was successful in a community setting. It has the potential to lead to healthy behavior modifications because participants adopted accurate risk perceptions. We identified a substantial number of at-risk individuals who could benefit from targeted prevention strategies, thus decreasing racial/ethnic cancer disparities.

The Use of Family Health Histories to Address Health Disparities in an African American Community

African Americans continue to suffer from health disparities. The Center for Minority Health (CMH) within the University of Pittsburgh has the mission to eliminate racial and ethnic health disparities. CMH has designed and implemented the Family Health History (FHH) Initiative. The FHH Initiative places genetic-counseling graduate students in the African American community to provide risk assessments and emphasize the importance of family history as it pertains to disease prevention. The FHH Initiative also allows participants to enroll into the Minority Research Recruitment Database (MRRD). This enables CMH to alert individuals to available research participation opportunities. In the first year of this program, 225 African Americans completed their family health histories. More than 60% of individuals enrolled in the MRRD. The authors report their initial successes and challenges of an initiative that incorporates awareness of family history information, proper screening guidelines, behavior-modification recommendations, and support for participation in clinical research.