Variants In Cancer Susceptibility Genes Research Articles

In This Issue

In This Issue

OP013: Landscape of germline pathogenic variants in cancer susceptibility genes in patients with sarcoma

Sarcomas are heterogenous mesenchymal tumors that mostly arise in bone or soft tissue. Sarcomas comprise only 1% of adult-onset cancers and over 20% of all pediatrics solid malignant cancers. The majority of sarcomas are soft tissue sarcoma and >40% of cases happen above age 65. Sarcoma is usually sporadic. Several rare cancer predisposition syndromes are associated with sarcoma such as Li-Fraumeni syndrome (LFS), Hereditary Retinoblastoma and Neurofibromatosis Type 1. These syndromes account for a small fraction of sarcomas.

EP048: Identifying cancer predisposition in a series of 1,521 pediatric oncology patients by tumor-only panel-based testing

Tumor-only profiling by next-generation sequencing (NGS) has been implemented in the pediatric oncology setting to enhance pathologic diagnosis, provide prognosis, and identify molecular targets for therapy. Clinically significant germline variants in cancer susceptibility genes covered by the assay will also be detected with this approach. Current guidelines regarding the threshold of triggering follow-up testing for germline pathogenic variants detected by tumor-only NGS are limited, given the challenge of distinguishing germline vs somatic variants as well as the need for follow-up germline confirmatory testing and genetic consultation.

Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing

Background:Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.Patients and methods:The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.Results:In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected.Conclusions:Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.

Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients of African ancestry

Since the discovery of the breast cancer susceptibility genes, BRCA1 and BRCA2, various other genes conferring an increased risk for breast cancer have been identified. Studies to evaluate sequence variants in cancer predisposition genes among women of African ancestry are limited and mostly focused on BRCA1 and BRCA2. To characterize germline sequence variants in cancer susceptibility genes, we analysed a cohort of 165 South African women of self-identified African ancestry diagnosed with breast cancer, who were unselected for family history of cancer. With the exception of four cases, all others were previously investigated for BRCA1 and BRCA2 deleterious variants, and were negative for pathogenic variants. We utilized the Illumina TruSight cancer panel for targeted sequencing of 94 cancer susceptibility genes. A total of 3.6% of patients carried a pathogenic/likely pathogenic variant in a known breast cancer susceptibility gene: 1.2% in BRCA1, 0.6% in each of BRCA2, ATM, CHEK2 and PALB, none of whom had any family history of breast cancer. The mean age of patients who carried deleterious variant in BRCA1/BRCA2 was 39 years and 8 months compared to 47 years and 3 months among women who carried a deleterious variant in other breast cancer susceptibility genes.

Cancer-Causative Mutations Occurring in Early Embryogenesis.

Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873.

Stakeholder attitudes towards establishing a national genomics registry of inherited cancer predisposition: a qualitative study.

This study aimed to describe the acceptability and perceived barriers and enablers to establish a national registry targeting carriers of pathogenic variants in cancer susceptibility genes from stakeholders' perspectives. Such a registry may effectively target carriers to translate existing research findings into optimised clinical care and provide a population-level resource for further clinical research and new gene and therapy discovery. In-depth interviews were conducted with individuals from four stakeholder groups: carriers of pathogenic variants, healthcare professionals, data custodians from the field of familial cancer, and heads of molecular pathology laboratories. Interview data were subjected to a qualitative analysis guided by a thematic analysis framework using NVivo software. A total of 28 individuals were interviewed: 11 carriers, 8 healthcare professionals, 5 laboratory heads, and 4 data custodians. All carriers and healthcare professionals were enthusiastic about the potential research applications of the registry. Carriers described that altruistic motivations provided the foundation of their support of the planned registry. Some carriers felt comfortable with a broad consent (consenting once, prospectively), while others preferred a narrow consent approach (consenting each time data is accessed). Some carriers and data custodians and registry developers also expressed a reluctance to link family member data without appropriate consent. Participants' enthusiasm and support for a national registry herald a productive and responsive research partnership once the registry has been established. Participants' views can be used to inform the approaches to be taken to develop and manage such a registry as an implicit codesign approach.

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM, CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion-negative RMS patients versus the patients with FOXO1 fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (TP53, NF1, DICER1, mismatch repair genes), rarely (BRCA2, CBL, CHEK2, SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53, BRCA2, mismatch repair) were on the ACMG Secondary Findings 2.0 list. In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.

Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Search Behavior Regarding Cancer Susceptibility Genes Using a Clinical Decision Support Tool for Gene-Specific Penetrance: Content Analysis.

BackgroundGenetic testing for germline cancer susceptibility genes is widely available. The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool that provides evidence-based risk predictions for individuals with pathogenic variants in cancer susceptibility genes.ObjectiveThe aim of this study was to understand the search behavior of the Ask2Me.org tool users, identify the patterns of queries entered, and discuss how to further improve the tool.MethodsWe analyzed the Ask2Me.org user-generated queries collected between December 12, 2018, and October 8, 2019. The gene frequencies of the user-generated queries were compared with previously published panel testing data to assess the correspondence between usage and prevalence of pathogenic variants. The frequencies of prior cancer in the user-generated queries were compared with the most recent US population–based cancer incidence.ResultsA total of 10,085 search queries were evaluated. The average age submitted in the queries was 48.8 (SD 16.5) years, and 84.1% (8478/10,085) of the submitted queries were for females. BRCA2 (1671/10,085, 16.6%), BRCA1 (1627/10,085, 16.1%), CHEK2 (994/10,085, 9.9%), ATM (662/10,085, 6.6%), and APC (492/10,085, 4.9%) were the top 5 genes searched by users. There was a strong linear correlation between genes queried by users and the frequency of pathogenic variants reported in published panel testing data (r=0.95, r2=0.90, P<.001). Over half of the queries (5343/10,085, 53.0%) included a prior personal history of cancer. The frequencies of prior cancers in the queries on females were strongly correlated with US cancer incidences (r=0.97, r2=0.95, P<.001), while the same correlation was weaker among the queries on males (r=0.69, r2=0.47, P=.02).ConclusionsThe patients entered in the Ask2Me.org tool are a representative cohort of patients with pathogenic variants in cancer susceptibility genes in the United States. While a majority of the queries were on breast cancer susceptibility genes, users also queried susceptibility genes with lower prevalence, which may represent a transformation from single gene testing to multigene panel testing. Owing to these changing tides, more efforts are needed to improve evidence-based clinical decision support tools to better aid clinicians and their practice.

Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population.

Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.

Uptake of genetic counseling and testing in a clinic based population of women with breast cancer.

10524 Background: Carriers of pathogenic variants in cancer susceptibility genes have an elevated risk of developing breast, ovarian, and other cancers.We conducted a medical record review to determine the uptake of genetic counseling and testing in a clinic-based population of women with breast cancer. Methods: Medical records of 150 women with breast cancer seen at the Karmanos Cancer Institute between January-December 2018 were reviewed to determine the proportion eligible for genetic testing according to National Comprehensive Cancer Network guidelines. We also assessed genetics referral rates, appointment completion and results of genetic testing. Using chi-square and ANOVA tests, we analyzed the association of demographic and clinical factors with eligibility and referral to genetic counseling. Results: The average age of diagnosis was 57.1 years old, with 68.7% of women diagnosed with stage I-III disease, and 31.3% diagnosed with stage IV disease. There were 91 (60.7%) women who met NCCN criteria for genetic testing, of which 46.2% ultimately underwent genetic testing. Eligible women were more likely to be younger (52.6 vs. 64.0 years old), White (75.0% vs. 54.5%), and have Medicaid (75.0%) or private insurance (72.9%) vs. Medicare (44.8%). Women who met NCCN criteria were 3.5 times more likely to be referred for genetic counseling than those that did not meet eligibility criteria. Women were also more likely to be referred if they had early-stage disease compared to stage IV (67.8% vs. 48.3%), and Medicaid or private insurance compared to Medicare (71.4%, 72.0% and 40.0%, respectively). Of eligible women, 59.3% had a genetic counseling appointment scheduled, and of those, 78.0% attended their appointment. There were no apparent differences in appointment completion based on race with similar percentages of Black and White women completing their appointments (74.0% and 77.0% respectively). Women with stage IV disease were more likely to complete their appointments (83.0%) compared to women with stages I-III (74.0%) and fewer women with Medicare completed their genetic counseling appointment (56.0%) compared to women with Medicaid (83.0%) and women with private insurance (83.0%). Among women who attended their appointment, 95.9% underwent genetic testing. Of women who had genetic testing, 8.5% had a pathogenic variant and 30.4% had a variant of unknown significance. Conclusions: The results of this study indicate that lack of genetic counseling referrals contribute to a gap between the need for and completion of genetic testing. By understanding barriers to genetic counseling and testing, future clinical initiatives could effectively improve accessibility to genetic counseling services.

Disease Spectrum of Breast Cancer Susceptibility Genes.

BackgroundPathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians.MethodsTwelve genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RECQL, STK11, and TP53), all of which have been conclusively established as BCSGs by the Clinical Genome Resource (ClinGen) and/or the NCCN guidelines, were investigated. The potential gene-disease associations for these 12 genes were verified and evaluated based on six genetic resources (ClinGen, NCCN, OMIM, Genetics Home Reference, GeneCards, and Gene-NCBI) and an additional literature review using a semiautomated natural language processing (NLP) abstract classification procedure.ResultsForty-two diseases were found to be associated with one or more of the 12 BCSGs for a total of 86 gene-disease associations, of which 90% (78/86) were verified by ClinGen and/or NCCN. Four gene-disease associations could not be verified by either ClinGen or NCCN but were verified by at least three of the other four genetic resources. Four gene-disease associations were verified by the NLP procedure alone.ConclusionThis study is unique in that it systematically investigates the reported disease spectrum of BCSGs by surveying multiple genetic resources and the literature with the aim of developing a single consolidated, comprehensive resource for clinicians. This innovative approach provides a general guide for evaluating gene-disease associations for BCSGs, potentially improving the clinical management of at-risk individuals.

CanRisk Tool-A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants.

The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations

Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of...

Predicted Chemotherapy Benefit for Breast Cancer Patients With Germline Pathogenic Variants in Cancer Susceptibility Genes.

Breast cancer patients increasingly undergo genetic testing. To examine chemotherapy indications for germline pathogenic variant (PV) carriers, we linked results of germline testing to Georgia and California Surveillance, Epidemiology, and End Results registry records, including 21-gene recurrence score (RS) results, for breast cancer patients diagnosed in 2013-2017. All statistical tests were 2-sided. Patients (N=37 349) had RS results of whom 714 had BRCA1, BRCA2, CHEK2, ATM, PALB2, or Lynch syndrome (MLH1, MSH2, MSH6, PMS2) PVs. For women aged 50 years or older at breast cancer diagnosis, RS often exceeded the chemotherapy benefit threshold (≥26) with BRCA1 (71.7% vs 14.4% with none; P <.001), PALB2 (37.1%; P = .001), and BRCA2 (44.3%; P < .001) PVs. Results were similar for women diagnosed at younger than 50 years of age. PVs in BRCA1, but not BRCA2, PALB2, ATM, CHEK2, or Lynch syndrome genes, were associated with elevated RS on multivariable analysis (P < .001). Results may inform RS testing decisions in breast cancer patients with PVs.

Abstract B043: Getting proximate: Facing the truth about African American hereditary breast cancer research – insight from Alabama

Abstract If there is any place to overcome research barriers it is Alabama. Known for being the site of one of the most unethical and inconceivable clinical studies - The Tuskegee Syphilis Study - and home of nearly double the national percentage of African Americans (AAs), history itself provides a substantial challenge. In Alabama, 85% of the counties are entirely medically underserved, most of which are rural, including the Alabama Black Belt, which is predominantly inhabited by AAs and associated with low economic status. Altogether, one can gather that getting proximate requires dedication, and considering all of the reported AA cancer health disparities, it is vital to address these barriers. Aiming to study hereditary breast cancer (BC) and other associated cancers in Alabama, we had to be adaptable and develop recruitment strategies appropriate for the community. In a recent publication, we described our initial efforts that were effective for recruiting AAs into the Alabama Hereditary Cancer Cohort (AHCC). A number of facets were key to this success, which included establishing community partners, educating and building trust in the community, and utilizing a recruitment bus, called the Gene Machine. As AA BC susceptibility is widely understudied, we realize the need to continue this effort; however, we recently went back to the drawing board and revamped our recruitment protocol in order to maximize our time and efficiency. We currently have over 150 AAs in the study and plan to bolster recruitment by implementing the protocol modifications. Ultimately, the goal of these rigorous efforts is to add to the limited, existing resources, i.e. biospecimens and genetic data, needed to better understand the science of cancer health disparities. When cancer-affected individuals enroll into our study, we carry out gene panel screening, initially searching for clinically significant variants in cancer susceptibility genes. Though our screening is currently research-based, through the development of our protocols, we felt it was important to offer the option to receive genetic research reports during the consent process. We had anticipated that many of our study participants would not have access to the care that provides such knowledge, and we have since confirmed that only ~20% of the cancer-affected AAs in the AHCC had previous clinical genetic screening. It was evident that most of those participants wanted such information with only 2% declining to be informed of the research results. Realizing that access to care is very limited in Alabama, we also established a collaborative telegenetic counseling project to provide services to mutation carriers in their local county health departments. Coupled together, these efforts attempt to provide study participants with a better understanding of disease risk and management, and allow integral genetic research to be carried out as we work towards reducing cancer health disparities. If there is any place to overcome barriers, it is here in Alabama and it is happening. Citation Format: Nancy Merner, Elizabeth Stallworth, Madison Bishop, Sophonie Omeler-Fenaud, Isaac McNeely, Anna Huskey. Getting proximate: Facing the truth about African American hereditary breast cancer research – insight from Alabama [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B043.

Comparing and assessing the reported penetrance of cancer susceptibility genes for breast cancer.

1520 Background: It is critical for oncologists to be aware of unbiased and interpretable cancer risks (i.e., penetrance) in carriers with germline pathogenic variants in cancer susceptibility genes. However, relevant literature is large and varies significantly in study design, patient ascertainment, and types of risk estimates reported. This heterogeneity can cause inconsistent conclusions between studies and create barriers for clinicians to understand and apply them in practice. To further understand the current literature, we assessed penetrance studies associated with non-BRCA breast cancer susceptibility genes based on study design and ascertainment adjustment. Methods: We used a validated natural language processing-based abstract classifier to identify all penetrance studies regarding eleven genes: ATM, BARD1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RECQL, STK11, and TP53. Relevant studies were then manually annotated as “with ascertainment adjustment” if a study was based on: (1) a general population; (2) a pedigree analysis or a family-based study with appropriate ascertainment adjustment; or (3) a hospital-based study or a panel testing analysis with well-matched cases and controls. Results: A total of 49 penetrance studies were identified, with a median of nine studies for each gene (range: 4-16). The case-control study was the dominant study type, accounting for over 80% in five genes, 50% in two genes, and 18% to 43% in the other four genes. The proportion of studies with ascertainment adjustment was generally low (mean: 33%) and varied widely between different genes (7% to 80%). Contradictory breast cancer risks (no increased risk vs. significantly increased risk) were found in eight genes (73%) (Table). The most common ascertainment bias identified was a case-control study with cases (patients) who had a strong family history but using general population controls. Conclusions: Ascertainment bias is common in penetrance studies, but few studies adjust for it appropriately. Clinicians should be aware of this issue, and new methods are warranted to select unbiased risk estimates, synthesize them, and provide the accurate general-population penetrance. [Table: see text]