Golafshar, Michael

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Sarcomas are rare heterogenous mesenchymal tumors with over seventy-five different subtypes, with varying biology and outcomes, with no clear inciting factor in the vast majority. To determine the prevalence of pathogenic germline variants (PGV) in patients with sarcomas, we undertook a prospective multi-site study of germline sequencing using an 84-gene next-generation sequencing panel among patients receiving care at the four Mayo Clinic Cancer Centers. Of 115 patients with bone and soft tissue sarcoma, the median age was 60 years, 49.6% were female, 82.6% were White. The anatomical location of the primary tumor included extremities (34.8%), retroperitoneum (19.1%), trunk (13.0%), and head and neck (7.8%). Family history of cancer was present in 62.6% of the study population. Ten patients (8.7%) had a pathogenic/likely pathogenic variant (PGV). Of these, three had stage IV sarcoma, and seven had earlier-stage sarcoma (stages I–III). Among the 55 (48.7%) patients who had variant of uncertain significance (VUS), 41.1% (22/55) had stage IV sarcoma and 58.9% (33/55) had earlier-stage disease. Of the ten patients with PGV, high-to-moderate penetrance gene abnormalities were identified in eight patients (80%) involving TP53 (3), BRCA1 (1), SDHA (1), ATM (2), and NBN (1) genes. The vast majority of the PGVs (70%) would not have been detected using the current guidelines. Because of the paucity of sarcomas and lack of effective treatment options for advanced disease, germline testing in sarcomas represents a potentially impactful strategy to assess therapeutic options and for assessment of familial risk.

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.

e22537 Background: Germline and tumor next-generation sequencing (NGS) are complementary tests whose benefit in capturing patients (pts) potentially eligible for precision therapies is maximized when the tests are paired, as qualifying pathogenic variants (PVs) are missed if either test was done in isolation (Lincoln et al. 2020). Germline NGS has the additional benefit of informing prevention through surveillance and cascade testing. We highlight the benefits of a universal approach to concurrent testing in a subset of the previously reported cohort of pan-cancer pts who underwent universal germline NGS (Samadder et al. 2020). Methods: Unselected pts with solid tumors underwent an 80+ gene germline panel and 315+ gene tumor panel. Variants in genes unique to the germline or tumor panels, including microsatellite instability (MSI) and tumor mutation burden (TMB), were also evaluated. Results: 104 pts [81.7% White, non-Hispanic, 71.2% male] with 23 cancer types [28% colorectal, 13% lung, 11% prostate, 49% other] were included. Five (5%) pts had no actionable tumor alterations or germline variants identified (Table). 18 pts (17%) had 19 pathogenic germline variants (PGVs) identified, 11 (58%) of which were detected on tumor NGS (Table). 92 pts had >1 tumor alteration identified, of which 12% were confirmed as PGVs (Table). Notably, tumor NGS revealed 81 pts (78%) pts with biomarkers that would could not have been identified with germline testing alone, such as variants in genes not on germline panel (80) or MSI-high (4), or TMB-high (21) status of the tumor. Conclusions: Germline and tumor NGS are complementary tests that often detect different actionable alterations. There is value in confirming both the presence and absence of somatic variants in the germline in order to make appropriate clinical recommendations for the patient and their family members. [Table: see text]

Abstract Two inherited autosomal dominant cancer predisposition conditions - BRCA related hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) - are termed Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a positive impact on public health. Selection of individuals for genetic testing for these conditions is based on personal and family history. The goal of this study was to evaluate whether screening in a tertiary medical center using exome sequencing could efficiently identify carriers of HBOC and LS and to determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines. Participants from three geographically diverse Mayo Clinic practices in the USA (Rochester MN, Phoenix AZ, Jacksonville FL) consented to clinical “Exome+” sequencing (Helix, San Mateo, CA; Mayo GeneGuide, Rochester, MN) in the TAPESTRY study (NCT05212428), which links sequencing data with electronic health records and the return of CDCT1 genetic findings. For this study we focused on two inherited cancer predisposition conditions: BRCA-related HBOC (BRCA1 and BRCA2) and LS (MLH1, MSH2, MSH6, PMS2 and EPCAM). Detailed chart review to collect demographic information, personal and family history, and assessment of clinical practice guidelines for genetic evaluation (National Cancer Control Network 2021). To date, 44,306 patients have enrolled and sequenced in TAPESTRY. Annotation and interpretation of all variants in 7 genes for HBOC and LS resulted in identification of 550 carriers (prevalence 1.24%) which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2 and 0.2% EPCAM). Demographics of the cohort included: 62.7% female, mean age 55.2 years, non-white race 9.6% and 3.8% Hispanic/Latino ethnicity. A personal history of cancer was present in 46.4% of test positive patients, including 22.5% of HBOC patients with breast or ovarian cancer and 20.9% of LS patients with colorectal or uterine cancer. More than half of the patients (52.1%) were newly diagnosed with HBOC and LS based on the results of this study. Overall, 39.2% of HBOC/LS carriers identified through Exome+ sequencing did not satisfy NCCN criteria for genetic evaluation, this was higher for LS (56.2%) compared to HBOC (32%). Amongst those newly diagnosed with HBOC/LS (n=286), NCCN criteria were not satisfied in 60% of cases (78% for LS and 51% for HBOC). Of the pathogenic germline variant carriers who met NCCN guidelines for testing, 34.2% were not aware of their diagnosis prior to participation in this study. Our results emphasize the need for wide genomic screening for CDCT1 cancer predisposition syndromes. Such screening could identify at-risk carriers of HBOC and LS, who would not otherwise be identified through clinical practice guidelines. Citation Format: Emily Gay, Niloy Jewel Samadder, Michelle L. Bublitz, Melanie M. Peterson, Tammy A. Wilson, Lorelei A. Bandel, Sebastian M. Armasu, Robert A. Vierkant, Matthew J. Ferber, Eric W. Klee, Nicholas B. Larson, Teresa M. Kruisselbrink, Timothy B. Curry, Jan B. Egan, Jennifer L. Kemppainen, Jessa S. Bidwell, Jennifer L. Anderson, Tammy M. McAllister, T'Nita S. Walker, Katie L. Kunze, Vanda Lindpere, Michael A. Golafshar, Margaret Klint, Richard J. Presutti, William V. Bobo, Aleksander Sekulic, Jolene M. Summer Bolster, Cheryl L. Willman, Konstantinos N. Lazaridis. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5768.

ObjectiveThis study describes the prevalence of pathogenic germline variants (PGVs) in head and neck cancer patients, the incremental yield compared to a guideline‐based approach to genetic evaluation, and the uptake of family variant testing.Study DesignProspective cohort study.SettingThree tertiary academic medical centers.MethodsGermline sequencing using an 84‐gene screening platform among unselected head and neck cancer patients who received care at Mayo Clinic Cancer Centers between April 2018 and March 2020.ResultsAmongst 200 patients, the median age was 62.0 years (Q1, Q3: 55, 71), 23.0% were female, 89.0% white/non‐Hispanic, 5.0% Hispanic/Latinx, 6% of another race, and 42.0% had prognostic stage IV disease. The most common subsites were the oropharyngeal (45.0%) and salivary glands (12.0%). The most common histology was squamous cell carcinoma (74.5%). Twenty‐one patients (10.5%) had a total of 22 PGVs; 20 of the 21 patients (95.2%) did not meet criteria for testing by current guidelines. Regarding penetrance of the 22 PGVs, 11 were high or moderate (most commonPMS2orHOXB13), and 11 were low or recessive (most commonMUTYH,WNR, orRECQL4). One patient had a change in care based on an identified PGV. Family variant testing was completed at a rate of 4.8%.ConclusionsUniversal gene panel testing identified a PGV in 10.5% of head and neck cancer patients; almost all would have been missed by current guideline‐based testing. One of 21 patients had a treatment change due to their PGV, indicating that head and neck cancer treatment decisions are not yet widely informed by germline alterations.Level of Evidence3Laryngoscope, 133:3378–3388, 2023

Abstract Hereditary factors play a role in the development of several cancers. Identification of germline predisposition can have implications for treatment and cancer prevention. While previous studies have found that universal multigene panel testing in patients with cancer yields increased detection of actionable heritable variants compared to targeted testing, patients belonging to racial and ethnic minority groups have been underrepresented in these studies. We undertook a prospective multi-site study of germline alternations among solid tumor cancer patients from under-represented minority (URM) populations receiving care at Mayo Clinic Comprehensive Cancer Centers between January 2020 and November 2022. Patients with a new or active cancer diagnosis (all stages) not selected for family history of cancer were tested with a &gt;80-gene next generation sequencing panel. Of 532 patients (mean [SD] age, 57.2 [12.7] years; 320 (60.2%) female), 247 (46.4%) were Hispanic/Latino, 130 (24.4%) Black/African American, 80 (15.0%) Asian, 66 (12.4%) American Indian/Alaskan Native, 2 (0.4%) Native Hawaiian/Pacific Islander, and 7 (1.3%) other. PGV were found in 43 patients (8.1%), including 29 moderate- or high- penetrance cancer susceptibility genes. Variants of uncertain significance (VUS) were found in 272 patients (51.1%). Of those with a PGV, 29 (67.4%) had incremental clinically actionable findings that would not have been detected by established testing criteria, of which 16 were moderate- or high-penetrance variants. Younger age of diagnosis, gender, race, ethnicity, and stage of disease were not predictive of PGV. In this study of under-represented minority cancer patients, universal genetic testing found that 1 in 12 patients harbor a PGV, more than two-thirds of whom would remain undetected using current guidelines. The paucity of genomic data in URM populations also results in a large proportion of VUS which may lead to under-estimation of disease associated variants. Table 1. Clinical and Demographic Characteristics of Included Patients Positive Negative VUS Total N (%) 43 217 272 532 (8.1%) (40.8%) (51.1%) Age - mean (SD) 53.7 57.0 57.8 57.2 (12.7) (12.6) (12.8) (12.7) Gender - Female 26 132 162 320 (60.5%) (60.8%) (59.6%) (60.2%) Race/Ethnicity Hispanic/Latino 24 110 113 247 (55.8%) (50.7%) (41.5%) (46.4%) Black/African 5 56 69 130 American (11.6%) (25.8%) (25.4%) (24.4%) Asian 10 (23.3%) 23 (10.6%) 47 (17.3%) 80 (15.0%) American Indian/Alaskan Native 4 (9.3%) 26 (12.0%) 36 (13.2%) 66 (12.4%) Native Hawaiian/Pacific Islander 0 (0.0%) 0 (0.0%) 2 (0.7%) 2 (0.4%) Other 0 (0.0%) 2 (0.9%) 5 (1.8%) 7 (1.3%) Tumor Types Breast 19 (44.2%) 80 (36.9%) 110 (40.4%) 209 (39.3%) CNS 1 (2.3%) 2 (0.9%) 1 (0.4%) 4 (0.8%) GI 7 (16.3%) 46 (21.2%) 58 (21.3%) 111 (20.9%) GU 8 (18.6%) 57 (26.3%) 62 (22.8%) 127 (23.9%) GYN 0 (0.0%) 8 (3.7%) 10 (3.7%) 18 (3.4%) Head/Neck 5 (11.6%) 8 (3.7%) 6 (2.2%) 19 (3.6%) Lung 0 (0.0%) 6 (2.8%) 11 (4.0%) 17 (3.2%) Melanoma 0 (0.0%) 2 (0.9%) 1 (0.4%) 3 (0.6%) Sarcoma 2 (4.7%) 4 (1.8%) 4 (1.5%) 10 (1.9%) Other 1 (2.3%) 4 (1.8%) 9 (3.3%) 14 (2.6%) Citation Format: Kevork A. Khadarian, Sailaja Pisipati, Jeremy C. Jones, Gerardo Colon-Otero, Donald W. Northfelt, Lindsey Gary, Idara U. Ekpoh, Giovanna G. Moreno, Edward D. Esplin, Robert Nussbaum, Brandie Heald, Margaret A. Klint, Kathleen A. Barrus, Tanios S. Bekaii-Saab, Aleksandar Sekulic, Michael A. Golafshar, Katie L. Kunze, Cheryl L. Willman, Konstantinos N. Lazaridis, Niloy Jewel Samadder. Universal genetic testing for hereditary cancer syndromes in an under-represented minority population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1921.

Abstract Sarcomas are rare heterogenous mesenchymal tumors with over 75 different subtypes, with varying biology and outcomes, with no clear inciting factor in the vast majority. The germline genetic susceptibility to sarcoma is not very well characterized. Identification of any underlying germline predisposition can have important implications for treatment of patients and screening recommendations for family members. To determine the prevalence of pathogenic germline variants (PGV) in patients with sarcomas, we undertook the Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study, a prospective multi-site study of germline sequencing using a &gt;80-gene next-generation sequencing platform. The study was done at the three Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. Patients were not selected based on stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no charge. Results: 115 adult patients with soft tissue sarcoma were included in the study. The median age was 60 years, 58.5% were male, 81% were White. The anatomical location of the primary tumor included extremities (33.0%), retroperitoneum (18.2%), trunk (12.2%), head and neck (7.8%). Family history of cancer was present in 63% of the study population. Ten patients (8.7%) had a PGV. Thirty percent of the patients with PGV had stage IV sarcoma (3/10), and 70% (7/10) had earlier stage sarcoma (stages I-III). Among patients who were found to have a variant of uncertain significance (VUS), 40% (22/55) had stage IV sarcoma and 60% (33/55) had earlier stage disease. Of the 10 patients with PGV, high to medium penetrance gene abnormalities were identified in 8 patients (80%) involving TP53 (3), BRCA1 (1), SDHA (1), ATM (2) and heterozygous deletion of NBN (1) genes. Of these PGV, gene deletions were observed in 6/10 while missense variants comprised the remaining 4. The vast majority of the PGV (70%) would not have been identified using the current guidelines utilizing the 2018 or 2020 National Comprehensive Cancer Network (NCCN), National Society of Genetic Counselors (NSGC) or American College of Medical Genetics and Genomics. Conclusion: In this prospective, multi-site study comprising over 100 patients with diverse sarcomas, unselected germline testing identified a PGV in 1 in 11 patients (8.7%) with the majority of these not being detected using current standard of care guidelines for genetic testing. Because of the rarity of sarcomas, in addition to limited effective treatment options for advanced disease, large scale germline testing in sarcomas represents a potentially impactful strategy to assess therapeutic options and for assessment of familial risk. Citation Format: Isaak Ailts, Michael A. Golafshar, Katie L. Kunze, Margaret Klint, Kathleen Barrus, Samuel Nussbaum, Edward Esplin, Brandie Leach, Sarah Young, Niloy Jewel Samadder, Mahesh Seetharam. Germline cancer susceptibility gene testing in unselected patients with soft tissue sarcoma: a multi-center prospective study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P056.