Genetic testing for a hereditary breast cancer predisposition has been available since 1996. Since then, many at-risk individuals have pursued testing for a variety of reasons including medical management, surgical decision-making, and family planning. However, as a result of the ability to learn ones cancer risk, women often struggle to incorporate this information into their lives and are faced with complex decision-making. Providing comprehensive services for this population that address these concerns is a matter of public health importance. This study documents the process of designing a support group for women who have tested positive for a hereditary breast cancer predisposition. Thirty-three women who have previously tested positive for mutations in BRCA1, BRCA2, or PTEN were invited to participate in a monthly support/discussion group and were sent questionnaires and informed consent documents for study participation. Nineteen of the thirty-three (57.6%) women responded, five (27.8%) were group participants and fourteen (72.2%) were non-participants. The questionnaire addressed experiences with cancer, management decisions, risk perceptions, existing levels of support, causes of anxiety, and communication with family members. As hypothesized, group participants had higher perceptions of breast cancer risk, lower confidence in medical management decisions, and less support from family and friends than non-participants. In addition, group participants were more likely to be younger, to have received their results 1-2 years ago, to not have a personal history of cancer, and to experience greater overall anxiety. Factors influencing perceived breast cancer risk and the need for support services included the number of first or second degree relatives with breast cancer, whether the relative was deceased or alive, the election of preventative surgery, and the time elapsed since result disclosure. Other findings included correlations between (a) perceived breast cancer risk and both perceived ovarian cancer risk and need for a support group, (b) perceived ovarian cancer risk and anxiety about talking with ones partner, and (c) all items addressing sources of anxiety. This study provides information that can potentially aid public health professionals who work with high-risk women and who are organizing or designing support services for women with a hereditary breast cancer predisposition.

Background: The genetic mechanisms that lead to head and neck squamous cell carcinoma (HNSCC) are incompletely understood. Cancer predisposition is associated with chromosome instability and hypersensitivity to DNA damaging agents. Fanconi anemia patients are extremely sensitive to crosslinking agents and are at increased risk of developing several cancers including leukemias, gynecological, and head and neck cancers. The Fanconi Anemia proteins (FANCs) are involved in pathways necessary for crosslink damage recognition and repair. Eight FANC proteins (A/B/C/F/G/I/J/L) assemble into a nuclear complex and two other proteins, FANCD1/BRCA2 and FANCD2 act downstream of the core complex. This FA protein complex is required for the monoubiquitination of the FANCD2 protein in response to DNA damage. By testing head and neck tumors for FANC characteristics, such as hypersensitivity to DNA crosslinking agents, increased chromosome breakage FANCD2 protein ubiquitination, formation of radial figures and genomic instability, we can determine whether this specific DNA damage repair pathway is intact in the tumors. Methods: Head and neck tumor cell lines were treated with the clastogenic crosslinking agent, diepoxybutane (DEB), and double-strand breaks and chromosomal aberrations were quantified. FANCA and FANCD2 cell lines were analyzed as positive controls and normal peripheral blood lymphocytes were used as negative controls. iv Findings: HNSCC cell lines treated with DEB have an increased number of DEB-induced double-strand breaks compared to normal lymphocytes, as evidenced by increased chromosomal breaks and tri- and quadriradials, suggesting defects in the DNA damage response. Interpretation: Patients who are hypersensitive to DNA damage are at increased risk of developing several types of cancer at an early age. Likewise, we predicted and showed that head and neck tumors have defects in the FANC pathway. This might suggest that the genes in the pathway either had germline or acquired alterations (mutations or regulatory defects), which could be tested by comparing normal cells from these patients to the tumor cells. Identifying and examining the mechanisms by which DNA damage occurs and is repaired can lead to a better understanding of genetic predisposition to cancer and to advances in early detection and treatment, therefore reducing morbidity and mortality. v

The Center for Minority Health (CMH) within the University of Pittsburgh has the mission to eliminate racial health disparities by 2010. One community-based intervention focuses on family health histories. Family health histories, or pedigrees, have been shown to be effective tools for identifying individuals at risk for common diseases who may benefit from increased screening or other risk reduction behaviors. Genetic counseling graduate students provide individuals with information pertaining to the importance of family history information in reducing the risk of chronic disease. Students travel to various locations in the African American community where they collect individuals family health histories. Individuals who participate have the opportunity to enroll in the Minority Research Recruitment Database from which they can be contacted regarding research for which they may qualify. This is the Centers effort to increase minority recruitment. This has public health relevance given that minorities are often under-represented in research and it is thought that increasing minority recruitment will aid in elimination of racial health disparities. This study was developed to characterize individuals who elected to enroll in the database and compare them to those who declined enrollment. Factors for comparison include demographics, recruitment variables, opinions regarding research, health care, personal health, and family history. Factors were assessed for 126 participants of which approximately 80% enrolled in the database and 20% declined. Analysis revealed that those more likely to participate in the database were female, without health insurance, more likely to respond to monetary incentives, more likely to talk to their physician about concerns for developing a disease, and less likely to have previously refused participation in a clinical trial. These results indicate that women are more likely than men to seek health information that pertains to their family history, incentives act as a motivation for individuals to enroll in this database, and issues of distrust may still act as a barrier to research participation for African Americans.

Acute lymphoblastic leukemia (ALL) is the most common malignancy occurring in childhood and accounts for 77% of all leukemia cases. Long-term survival is greater than 80% with appropriate treatment. Chemotherapy is the most widely used treatment, but it can have significant side effects including neutropenia and immunosuppression. Interleukin (IL-10) is an immunoregulatory cytokine with anti-inflammatory effects. It inhibits some cells like macrophages while stimulating other cells like B cells. IL-10 has been found to be involved in conditions involving an immune response and inflammation, including pneumonia, septic shock, and graft versus host disease (GVHD). Myeloperoxidase (MPO), which catalyzes the production of hypochlorite from chlorides and hydrogen peroxide, is an abundantly expressed hemoprotein with anti-microbial effects and a major player in host defense. MPO has been implicated in the pathogenesis of a number of conditions and associated with certain infections. In this study, polymorphisms in MPO and IL-10 were investigated to test their association with risk of infection in a population of Caucasian patients with ALL. Genotyping was performed by enzyme digest for IL-10 polymorphism -592(C/A) and by pyrosequencing for the MPO polymorphisms -129(G/A) and -463(G/A). Allele frequencies at each site were in Hardy Weinberg Equilibrium (HWE). No significant correlation was found between the genotype at IL-10 -592, MPO -129 or MPO -643 and infection episodes in our patient population. As the study population was relatively small, no strong conclusions can be drawn, but implications for further research can be identified. Public Health Significance: Knowledge of the effects of certain genetic polymorphisms may be important when treating patients with ALL. Patients at increased risk of infection may require prophylaxis or more intense surveillance to ensure a better outcome.

Graduation date: 1951

The prediction of wellness factors on alcohol consumption and behaviors related to alcohol among college students

Sickle cell trait carriers are healthy; however, they are at risk to have children with sickle cell disease (SCD), a serious hematologic disorder. Unsuccessful population screening for sickle cell trait (SCT) has resulted in a large population of African American individuals entering childbearing age with no knowledge of their risk. Recent experience with newborn screening follow-up of hemoglobinopathies has shown that interest in genetic screening for SCT is low. This study aims to understand and increase the level of acceptance of genetic screening among the African American population through a program of education and assessment of the current state of SCD cultural health beliefs. This is important for Public Health because SCD is the most common genetic disorder affecting the African American community and education to promote screening must be sensitive to the cultural beliefs of the community. Utilizing a method of anonymous surveys given to female African American patients within a busy prenatal clinic the effect of education of SCD on the acceptance of genetic screening for SCT has been assessed. The Health Belief Model was used to assess the current state of health beliefs regarding SCD and trait testing through anonymous surveys. This study revealed that a brief educational intervention regarding SCD in a prenatal setting is effective in significantly increasing knowledge of SCD and acceptance of screening for SCT (p-value < 0.001). African American women of childbearing age have a high perception of severity of SCD, a low perception of susceptibility to SCD, a high perception of benefit to SCT testing and a low perception of barriers to testing for SCT. Education within a prenatal setting can be used as a model to increase acceptance of screening for SCT. A high level of knowledge of SCD is associated with a high level of acceptance; however, the Health Belief Model revealed that currently the majority of the participants do not feel that they are personally at risk to have a child with SCD, regardless of SCD knowledge. Future education of SCD must take into account these beliefs in order to effectively motivate interest in SCT testing.

Prenatally detected chromosomal mosaicism complicates genetic counseling as there is variability in phenotypic outcome and available information pertaining to phenotypic consequences is limited. The objective of this study was to identify the phenotypic effects of mosaicism that was diagnosed prenatally. A total of 4,599 CVS specimens and 15,688 amniocentesis specimens were collected between 1991 and 2005 and clinical information was reviewed for all mosaic cases. Of those procedures, 76 CVS specimens (1.65%) and 66 amniocentesis specimens (0.42%) indicated a mosaic result. However, seven of the mosaic amniocentesis results were observed after a previous mosaic CVS result. When these specimens were removed from the calculation, the incidence of mosaic amniocenteses was 0.38%. Of the cases that had follow-up cytogenetic testing, CVS cases were found to have a true mosaicism rate of 23.6% while amniocentesis cases had a rate of 60.7%. The rates of prenatally detected mosaicism and true fetal mosaicism for Magee-Womens Hospital are comparable to the rates reported in literature. This study found mosaic results involving trisomy for chromosomes 2, 7, 8, 9, 10, 12, 13, 15, 16, 18, 20, 21, 22, X, and Y. In addition, there was monosomy for chromosomes 21, 22, and X, tetraploidy, structural aberrations, and supernumerary marker chromosomes. However, no cases of UPD were identified. From this information, associations were made between the phenotypic outcomes observed in this study and those reported from previous studies. Based on the information provided from this study, it is apparent that phenotype can vary, even when the same abnormality is involved and that more information is needed regarding long term consequences of prenatally diagnosed mosaicism. The results of this study are important to public health because it provides additional data regarding the phenotypic results after prenatal diagnosis of mosaicism for various chromosome abnormalities and increases the understanding of the role of mosaicism in prenatal diagnosis, enabling more effective patient counseling.

Type 1 diabetes mellitus is a multifactorial autoimmune disease caused by a combination of genetic and environmental factors. Further knowledge and understanding about the genes which play a role in type 1 diabetes has a clear public health significance in that it will aid in the prediction, treatment and a possible cure. Type 1 diabetes is a chronic disease with a lengthy preclinical course, which eventually results in pancreatic beta cell destruction and inability of the body to produce insulin hormone. Type 1 diabetic patients generally require exogenous insulin to survive. Several genetic loci have been proposed to be linked to type 1 diabetes; however, the HLA and VNTR regions are currently believed to account for the majority of genetic risk, contributing to about 42% and 10% of an individuals risk to develop type 1 diabetes, respectively. This study focuses on the candidate gene Islet Cell Autoantigen 1 (ICA1), which codes for the protein ICA69. This protein product is expressed in the islets of Langerhans, the neuroendocrine system and in the thymic medulla; this last location is an area of the body known to play a major role in immunologic tolerance. Preliminary studies in the NOD and B6 mouse models suggest that a SNP within the promoter region of Ica1 affects transcription and may account for altered expression in the thymus. Our current study aimed to determine whether single nucleotide polymorphisms within intronic regions of the human ICA1 gene differed between a diabetic case population and non-diabetic controls. It was hypothesized that SNPs within the ICA1 gene differ between cases and controls and play a role in the onset of type 1 diabetes. Polymerase Chain Reaction (PCR) was applied for DNA amplification and the pyrosequencing technique was used to genotype all samples. At SNP location rs2058519 there was a clear genotypic difference between the cases and controls (p= .0003). These results suggest that genetic variation at this specific SNP location in the ICA1 may be associated with type 1 diabetes susceptibility. The ultimate goal of this study is to determine whether our candidate gene ICA1 appears to play a role in the pathogenesis of type 1 diabetes.

Genetic counselors are health professionals specially trained in medical genetics and counseling. Twenty-nine masters level genetic counseling training programs exist in North America and collectively admit approximately 195 students each year. Continuation of the education and training of these specialized health professionals has significant public health importance. The existing admissions process has recently proven to be labor intensive and time consuming, with difficulty encountered while trying to fill programs. As a result of these obstacles, an alternative admissions procedure was explored. The match algorithm used by U.S. medical residency programs was used as a basis for this study. Under this system, software utilizes rank order lists submitted by programs and applicants to place the two parties into the most mutually beneficial program-applicant pairings. Twenty-seven genetic counseling programs and 166 current first year students participated in a survey that gathered program and student preferences. In addition, interest, opinions, and suggestions concerning the existing and proposed admissions system were ascertained. Due to incomplete student participation in the study, the U.S. residency match algorithm was modified. Compared with the existing admissions process, the match resulted in more programs (4 of 27) with unfilled slots, and approximately equal student satisfaction in terms of which program they were matched to. The accuracy of the modified match results is limited due to the match modifications and insufficient number of study participants. The majority of students (66%) indicated they would not be willing to participate in a match and 75% indicated they were satisfied or very satisfied with the existing admissions process. Program directors were largely satisfied with the existing process (81%). Benefits of a match may include: time efficiency, reduction in anxiety, and ease of process. Both students and program directors perceived barriers to the implementation of a match, including the problem of financial aid distribution under a match, the operating costs, and loss of decision making ability. Both groups suggested improvements for the existing admissions process. Suggestions included introduction of a universal application and an earlier notification date for admissions decisions. This study serves as a collection of data to be used for further investigation into the use of a matching algorithm in genetic counseling admissions.