This Is AuburnElectronic Theses and Dissertations

The establishment of the Alabama Hereditary Cancer Cohort and genetic analysis




Bishop, Madison

Type of Degree

PhD Dissertation




Inherited genetic risk factors in known breast cancer (BC) susceptibility genes increase an individual’s overall lifetime risk of developing BC and are estimated to contribute towards approximately 35% of hereditary BC cases. Although next-generation sequencing (NGS) gene panels have been implemented into the clinic to improve BC survival for individuals carrying known genetic risk factors, there is a concern that clinically accredited NGS gene panels contain genes lacking clinical validity and utility. Furthermore, groups that are most susceptible to health and healthcare disparities, such as African Americans, have been underrepresented in medical research and less information is known about hereditary cancer genetics in such populations. Therefore, it is imperative to explore adaptive approaches to recruitment and enroll underrepresented individuals into research studies to assess the complete contribution of risk variants in known cancer susceptibility genes using research-based NGS gene panels. The research efforts described herein highlight the mechanisms used to establish the Alabama Hereditary Cancer Cohort (AHCC) and the subsequent genetic analysis using a research-based NGS gene panel, B.O.P. (Breast, Ovarian, and Prostate) to evaluate the genetic risk of BC, ovarian cancer (OvC) and/or prostate cancer (PC) in different ethnicities. Over a three-year period using two essential approaches, hospital and community-based recruitment (CBR), 242 individuals were enrolled into the AHCC. Although both recruitment mechanisms were instrumental, the unique trust building, educational, and traveling components of CBR dramatically facilitated the enrollment of African Americans resulting in large families for genetic analyses. The first B.O.P screening involved 43 cancer-affected individuals from the AHCC. The purpose of this screening was to analytically assess the B.O.P. gene panel. Upon bioinformatics processing and variant filtering, called variants were validated using polymerase chain reactions (PCR) and Sanger sequencing. Subsequently, 61 of 74 variants were validated and classified as true positives (TPs). TPs had an average sequencing depth of 659X and alternate allele frequency of 51%, whereas the average false positive (FP) sequencing depth was 34X and alternate allele frequency was 33%. Although low sequencing depth was not always indicative of a FP, high sequencing depths (>100X) signified a TP. Overall, the initial B.O.P. screening enabled the establishment of criteria to alleviate future validation efforts and strongly supported the use of B.O.P. to further explain hereditary cancer susceptibility. Subsequent B.O.P. screening of 97 BC-affected individuals of African and European descent from the AHCC provided essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities. Although there were no significant differences between the ethnicities regarding damaging variants, African American BC cases were more likely to have seemingly benign variants compared to European American BC cases, which could explain ethnic-specific risk. Continued B.O.P. screening will elucidate BC genetics that may explain current disparities and, ultimately, impact the clinical validity/utility of clinically-accredited NGS gene panels.