bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of oncolytic herpes simplex virus on fusion-positive rhabdomyosarcoma to radiotherapy.
Authors: Shaikh Maryam G. , Nazam Nazia , Butey Swatika , Erwin Michael H , Stewart Jerry E. , Aye Jamie , Beierle Elizabeth A 
Published: June 2024

10063 Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite multimodal interventions including surgery, chemotherapy, and radiotherapy, nearly a third of patients with localized disease will experience tumor recurrence. Patients with tumors harboring an oncogenic FOXO1 fusion are at greater risk of relapse and are most in need of novel therapies. Oncolytic viruses are being explored as treatments for pediatric tumors, and data suggest that oncolytic viruses may enhance responses to chemoradiotherapy. M002 is a genetically engineered oncolytic herpes simplex virus (oHSV) that exhibits aneurovirulence in normal cells. M002 selectively replicates in malignant cells, eliminating these cells through cellular burst during the lytic cycle. In the present study, we explored the efficacy of the M002 virus alone and in combination with low-dose ionizing radiotherapy in a human patient-derived xenograft (PDX) model of fusion-positive RMS (FP-RMS). Methods: A human FP-RMS PDX was established and maintained by injection into the quadriceps femoris muscle of athymic nude mice under Institutional Animal Care and Use Committee guidelines (IACUC-09363). Tumors were dissociated and cells were treated with increasing multiplicity of infection (MOI) of either the oHSV, R3659 or its genetically engineered variant, M002. A colorimetric assay evaluated the cytotoxicity of oHSV treatments on the RMS PDX cells after 24, 48, and 72 hours of infection. In separate experiments, cells treated with vehicle (control) or infected with M002 were exposed to irradiation (2 Gy), and viability was determined at 24, 48, 72, and 96 hours. Results: Treatment with M002 or its parent construct, R3659, significantly reduced RMS PDX cell viability in a dose-dependent manner at all time points. M002 showed slightly higher cytotoxicity than R3659 as measured by lethal dose 50% (LD50, 37±1.25 vs 44±0.95 PFU/cell, M002 vs R3659, at 24 hours, p=0.02). When sub-lethal doses of M002 were combined with low-dose irradiation, RMS PDX cell viability was significantly decreased compared to cells treated with either M002 or irradiation alone (26% decrease at 10 PFU/cell). Conclusions: Our preliminary data highlight that M002 exhibits cytotoxicity in a PDX model of FP-RMS. Treatment with M002 further increased the cytotoxicity of ionizing radiation compared to individual treatments, suggesting that oHSV sensitized the cells to radiotherapy. Future studies in vivo may provide more pre-clinical evidence for the radio-sensitizing and therapeutic potential of M002 in FP-RMS.
Evaluation of a polygenic risk score as a predictor of early onset triple-negative breast cancer in Black women.
Authors: Pederson Holly Jane , Hu Eudora , Kucera Matthew , Hullinger Brooke , Simmons Timothy , Hughes Elisha 
Published: June 2024

10501 Background: Black women in the U.S. often develop early, biologically aggressive breast cancer (BC). Triple-negative breast cancer (TNBC) is a particularly aggressive type that occurs more frequently in Black than white women and often develops before recommended regular screening. More accurate risk prediction methods are urgently needed to identify young Black women with elevated risk of TNBC. Incorporating polygenic risk scores (PRS) into clinical models can substantially improve risk assessment, but most PRS have demonstrated poor performance among non-European ancestries. We previously described a multiple-ancestry PRS (MA-PRS), based on 56 ancestry-informative and 329 BC-associated single-nucleotide polymorphisms (SNPs), that predicts overall BC risk for diverse populations by characterizing genetic ancestry at each BC SNP and applying ancestry-specific SNP risks and frequencies. Here, we evaluated the extent to which MA-PRS improves upon clinical factors for the prediction of TNBC and early onset ( < 50 years) TNBC in a large, independent cohort of self-reported Black women. Methods: We examined clinical and genetic records from self-reported Black women referred for hereditary cancer testing from 8/22 - 9/23 and negative for pathogenic variants in BC-associated genes. The association of MA-PRS with TNBC was analyzed using multivariable logistic regression adjusted for personal and family cancer history, age and genetic ancestry. Analyses were conducted within the full cohort and the subpopulation of patients < 50 years old. Odds ratios (OR) are reported per standard deviation (SD) with 95% confidence intervals (CI). Results: We identified 14728 Black women who met study eligibility criteria. Nearly 70% (9895/14728) of patients were under the age of 50. In the full cohort, 629 (4.3%) patients were diagnosed with TNBC, and 173 (1.7%) were younger than 50 years old. MA-PRS significantly improved TNBC risk prediction over clinical factors in the full cohort and in the subpopulation of women under 50 (Table). The effect of MA-PRS on risk stratification was comparable to the 1.4 OR per SD reported in current literature for mammographic density, which is widely recognized as an important risk factor. Women in the top 5% of the MA-PRS distribution were at roughly 2-fold increased risk of TNBC (Table). Conclusions: MA-PRS substantially improved upon clinical factors for the prediction of TNBC and early-onset TNBC in a large cohort of Black women. MA-PRS appears to be equally as important for managing risk of early-onset TNBC as mammographic density for overall BC. Incorporation of MA-PRS into BC risk assessment has the potential to improve TNBC survival through more accurate identification of women at high risk. [Table: see text]
Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants.
Authors: Couch Fergus , Huang Huaizhi , Pesaran Tina , Karam Rachid , Yadav Siddhartha , Domchek Susan M. , Monteiro Alvaro N.A. , Boddicker Nicholas J. , Chen Wenan , Richardson Marcy E , Hu Chunling 
Published: June 2024

10511 Background: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n > 4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing (SGE)-based functional characterization of 97% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot encoded by exons 15 to 26 for pathogenic missense variants. Methods: SGE of exons 15 to 26 of BRCA2(MANE transcript ENST00000380152.8) was performed in the haploid human HAP1 cell line. Each exon along with 10bp flanking intronic sequence was studied as an independent target region. The most efficient sgRNA for each target region was selected and cloned into a Cas9 expressing plasmid. Site-saturation mutagenesis (SSM) libraries for each of the 14 target regions were designed to target every nucleotide and were generated by site directed mutagenesis using NNN-tailed PCR primers. HAP1 cells were transfected and harvested at Day5 and 14. Cell survival in response to each variant was assessed based on deep sequence analysis of the surviving endogenously targeted HAP1 cells at Day 5 and Day 14. Results: A total of 7013 SNVs were characterized as functionally abnormal (n = 955), intermediate/uncertain, or functionally normal (n = 5224) based on 95% precision for ClinVar known pathogenic and benign standards. Results were validated relative to batches of nonsense and synonymous variants and variants evaluated using a homology directed repair (HDR) functional assay. Breast cancer case-control association studies showed that pooled SNVs encoding functionally abnormal missense variants were associated with increased risk of breast cancer (odds ratio (OR) 3.89, 95%CI: 2.77-5.51). The functional data were added to other sources of information in a ClinGen/ACMG/AMP-like model and 700 functionally abnormal SNVs, including 220 missense SNVs, were classified as pathogenic or likely pathogenic, while 4862 functionally normal SNVs, including 3084 missense SNVs, were classified as benign or likely benign. Conclusions: The production of functional maps for 97% of all SNVs in the BRCA2 DBD allowed for separation of nucleotide/protein-level functional aberrations. When coupled with genetic and clinical sources of evidence this study led to clinical classification of 5500 individual variants. These data will prove useful in the future, through integration with other datasets, for characterization and clinical classification of all variants in this region in individuals from all racial and ethnic backgrounds and for all BRCA2 associated forms of cancer.
Real-world cancer care utilization among patients with breast cancer with germline variants of uncertain significance.
Authors: Kurian Allison W. , Hughes Kevin S. , Nielsen Young Sarah M. , Russell Emily M. , Facio Flavia , Moretz Chad , Ellsworth Rachel , Pineda Alvarez Daniel Esteban , Esplin Ed , Korn W. Michael 
Published: June 2024

10512 Background: Receipt of variant of uncertain significance (VUS) results from germline genetic testing (GGT) is common, but should not influence treatment or surveillance interventions. We examined treatment and surveillance uptake among breast (BC) patients (pts) undergoing GGT. Methods: GGT (Invitae Corporation) and insurance claims (Komodo Healthcare Map) data were assembled for female pts with ICD code(s) for BC or DCIS from 2015-2023, GGT <120 days post-diagnosis (dx) and >1 year of claims pre- and post-GGT. Inclusion/exclusion criteria followed prior work (PMID 32027353). Genes analyzed for VUS and positive (>1 pathogenic germline variant, PGV) results were those with high ( > 50%; BRCA1/ 2, CDH1, PALB2, PTEN, TP53) or moderate (20-50%; ATM, BARD1, CHEK2, NF1, STK11, RAD51C/D) BC risk. Multivariable logistic regression models of the association between GGT results and interventions included race/ethnicity, age, family history, local/distant metastasis, and log-transformed time from BC dx to GGT. Chi-square tests were used to compare demographics of VUS pts to other pts. Significance was set to p < 0.05. Results: The cohort consisted of 19,334 pts (2005 VUS, 16,062 negative, 1,267 positive): 68% White, 25% lymph node involvement, 63% cancer family history, 28% Medicare/Medicaid, mean (SD) age at testing: 53 (11) and mean (SD) days from dx to GGT: 37 (25). VUS pts were more likely to be non-White (p < 0.001). VUS pts were not more likely than negative pts to undergo BC-related therapies or surveillance, except for (anthracycline) chemotherapy (Table). In contrast, positive pts had significantly greater odds than negative pts of bilateral mastectomy, platinum/anthracycline chemotherapy, PARP inhibitors, and breast MRI. Conclusions: In a contemporary, real-world cohort of nearly 20,000 BC patients, receipt of BC-related interventions was similar in VUS and negative pts. VUS results do not appear to prompt guideline-discordant management, though the finding of increased anthracycline use needs further study. [Table: see text]
Tracking uncertainty in germline genetic testing for hereditary cancer syndromes: Sources, attributes, and resolution of variants of uncertain significance in over 1 million individuals.
Authors: Reys Brian , Johnson Britt , Chen Elaine , Kobayashi Yuya , Facio Flavia , Ting Yi-Lee E , Nielsen Young Sarah M. , Esplin Ed , Hatchell Kathryn E. , Aguillar Sienna E , Ouyang Karen E , Korn W. Michael , Aradhya Swaroop E , Pirzadeh-Miller Sara 
Published: June 2024

10513 Background: Genetic testing for hereditary cancer syndromes has diagnostic, prognostic and therapeutic implications; however, variant(s) of uncertain significance (VUS) are not clinically actionable. As such, VUS are a challenge to the entire medical community. Additionally, individuals from underrepresented race, ethnicity, and ancestry (REA) groups are disproportionately impacted by VUS. This study reports on the prevalence of VUS in patients referred for genetic testing for hereditary cancer syndromes and the results of reclassification. Methods: Patients were referred for diagnostic multigene panel testing for hereditary cancer from September 2014 to September 2022. Variants were classified as benign (B), likely benign (LB), VUS, likely pathogenic (LP), or pathogenic (P) using Sherloc, a validated system based on guidelines from ACMG/AMP. Both the number of unique VUS (uVUS) and the number of times they were observed in individuals (oVUS) were counted. All-time uVUS were separated as being reclassified and non-reclassified, and the relative contribution of evidence types used for reclassification was analyzed. Results: During this 8-year period, 1,122,444 unrelated individuals were tested for hereditary cancer with a mean number of 53 genes tested per individual. Results showed a mean of 0.45 oVUS per individual; 30.6% of individuals without a P/LP variant had at least 1 oVUS. The rate of oVUS normalized to the number of genes tested was highest in French Canadian and lowest in Ashkenazi Jewish individuals, as the mean number of genes sequenced to observe one VUS was 39.8 and 59.4, respectively. White individuals had a lower oVUS rate of 31.4% than Sephardic Jewish (53.8%), Asian (48.3%), Black (40.5%), Hispanic (37.6%), and additional underrepresented REA groups. In total, 7,542 (7.3%) of 103,767 uVUS were reclassified, affecting 88,877 individuals (7.9%); 5,864 (77.8%) of the reclassified uVUS were downgraded to B/LB, and 1,678 (22.2%) were upgraded to LP/P. Evidence from clinical observation contributed the most for upgrading uVUS (16.0-fold compared to non-reclassified uVUS), while evidence from experimental studies contributed the most to downgrading uVUS (23.9-fold). Conclusions: Experimental studies and clinical evidence were the most impactful types of evidence for reclassifications. This highlights the partnership among researchers, clinicians, and laboratories to resolve VUS. Further representation of diverse REA groups in genomic databases is needed to address the disparities in VUS rates, and additional research is needed into methods that could expedite the resolution of VUS so that patients can make more informed decisions.
Impact of the oral contraceptive pill on the rate of ovarian cancer incidence in different races of women.
Authors: Hedin Tosha , Desai Poorvi Kirit , Manji Faiza 
Published: June 2024

10521 Background: The rate of ovarian cancer incidence has drastically decreased over the years, though it is the fifth most leading cause of cancer death in women. Oral contraceptive pills (OCP) are a major cause for the decline due to decreasing the number of ovulations in a woman’s lifetime. In fact, women who have ever used OCPs have a 30-50% lower risk of ovarian cancer incidence compared to women who have never used OCP. This study compares the use of OCP in different races of women and its effect on the decline in incidence of ovarian cancer. Methods: The average rate of incidence per 100,000 cases per year for ovarian cancer in White, Asian and Black females was obtained from the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program SEER*Stat Database: NPCR and SEER Incidence – U.S. Cancer Statistics 2001–2019 Public Use Research Database. The National Center for Health Statistics, National Survey of Family Growth was used to find ever use of OCP among sexually experienced women ages 15–49 in the United States for 2002 and 2015-2019. Results: White women, in the year 2002 and 2019 had a rate of ever OCP use of 87% and 87.5% respectively. During that same time period, they had the most drastic decrease in ovarian cancer incidence of 43%, compared to Black and Asian female population. In 2002, the incidence rate of ovarian cancer for White women was 14.6 per 100,000. 17 years later, in 2019, it dropped to 10.2 per 100,000. Black women had the second highest ever use of OCP and the second highest rate of change for ovarian cancer incidence. In 2002, 79.1% of Black women had ever used OCPs compared to 73% in 2019. In 17 years, the incidence rate per 100,00 decreased 39% for Black women. Incidence rate per 100,000 in 2002 was 10.4 and incidence rate in 2019 was 7.5 per 100,000. Asian women comparatively had the lowest ever use of OCP and the lowest rate of change for ovarian cancer incidence. Data was not available for 2002, but in 2019, Asian women’s ever use of OCP was 65.6%. Incidence of ovarian cancer for Asian women decreased by 21% between the years 2002 to 2019. Rate per 100,000 was 10.8 in 2002 and decreased to 8.9 per 100,000 in 2019. Conclusions: The oral contraceptive pill was made available in the year 1960. Since then, it has been a large factor as to why ovarian cancer incidence has declined. Healthcare disparities and cultural differences play a part in the rate of OCP use across different races of women. This, in turn, leads to varying levels of ovarian cancer incidence decline with White women having the highest rate, followed by Black, then Asian women. Ovarian cancer has a high mortality due to inadequate screening techniques and late diagnosis which is perpetuated by cultural barriers to receiving care. A decreased risk of ovarian cancer should be considered as a benefit when prescribing OCPs and a protective factor among all studied races.
Impact of colorectal cancer screening on the incidence of advanced stages of the disease in the United States: An analysis of 181,442 patients.
Authors: Ilerhunmwuwa Nosakhare Paul , Uche Ifeanyi , Wasifuddin Mustafa 
Published: June 2024

10524 Background: Routine cancer screening, in addition to identifying early-stage cancers, aim to delay the time of diagnosis of the advanced stage. The impact of screening on the incidence of advanced colorectal cancer (aCC) in real-world settings is unknown. Methods: Data of adults aged 50–74 years with regional/distant stage (advanced) colorectal cancer diagnosed between 2004 and 2020 was obtained from the Surveillance, Epidemiology, and End Results Plus Data, 17 Research Plus Registries. The age-standardized incidence rates (ASIR) and annual percentage change (APC) were used to compare incidence trends stratified by sex, race/ethnicity, area of residence, and tumor site. Results: Among 181,442 cases of aCC, 56.6% were male, 117 847 (65%) were Non-Hispanic White (NHW), 23 419 (12.9%) were Non-Hispanic Black (NHB), 22 402 (12.4%) were Hispanics, 15 787 (8.7%) were Non-Hispanic Asian or Pacific Islander (NHAPI), 1564 (0.9%) were Non-Hispanic American Indian/Alaska Native (NHAIA), and 423 (0.2%) were of unknown race, respectively. In 123 609 cases (68.1%), the tumor site was in the colon, in the rectum in 41 395 cases (22.8%), and in the recto-sigmoid junction in 16 438 cases (9.1%). From 2004 to 2020, overall ASIR of aCC decreased (APC, -1.87%: -2.37 to -1.40), especially in females (APC, -2.05%: -2.53 to -1.55 vs. male: APC, -1.84%: -2.36 to -1.29), and metropolitan residents (APC, -2.01%: -2.57 to -1.43 vs. non-metropolitan: APC, -1.36%: -1.78 to -0.92). Notably, NHB showed the greatest decrease (APC, -2.56%: -3.01 to -2.06) followed by NHW (APC, -1.95%: -2.44 to -1.47), NHAPI (APC, -1.80%: -2.25 to -1.32) and Hispanics (APC, -1.29%: -1.85 to -0.64). There was no significant change in the ASIR among NHAIA. Furthermore, the ASIR of advanced colonic (APC, -2.66%: -3.18 to -2.14) and recto-sigmoid cancers (APC, -2.35%: -2.91 to -1.65) declined, but advanced rectal cancer increased (APC, 0.58%: 0.18 to 0.98) over the same period. Conclusions: This study highlights the positive impact of colorectal cancer screening in reducing aCC incidence rates in across genders, residential areas, and racial groups/ethnicities including minority populations. While there may be other contributing factors, increased awareness and use of screening may account for the overall declining aCC incidence rates over the almost 20-year study period. Further research is essential to identify factors contributing to the screening program's limited impact on the NHAIA population and advanced rectal cancers. [Table: see text]
The utility of HPV16 E6 as a potential biomarker for HPV-related cancers in HIV-infected men who have sex with men.
Authors: Ando Naokatsu , Mizushima Daisuke , Hoshino Haru , Takano Misao , Aoki Takahiro , Watanabe Koji , Nakamoto Takato , Kawashima Akira , Abe Seitaro , Michels Birgitta E , Waterboer Tim , Gatanaga Hiroyuki 
Published: June 2024

10526 Background: The burden of HPV-related cancers, including oropharyngeal and anal cancers, poses a significant challenge. Although recent advancements in screening for anal cancer have been made for HIV-infected men who have sex with men (HIV-MSM), establishing effective screening protocols for oropharyngeal cancer remains ongoing. The early oncoprotein HPV16 E6 presents as a promising biomarker for the detection of HPV-associated cancers in this population as well. We investigated the utility of HPV16 E6 in HIV-MSM. Methods: We conducted a retrospective study using an HIV cohort at the AIDS Clinical Center of the National Center for Global Health and Medicine. Participants were all HIV-MSM and included those with HPV-related cancers or precancerous lesions such as oropharyngeal cancer, anal cancer, anal high-grade squamous intraepithelial lesions (aHSIL), and anal low-grade squamous intraepithelial lesions (aLSIL). All cancers and precancerous lesions were histologically confirmed. Frozen plasma samples taken at the time of diagnosis were evaluated. Additionally, when available, samples were retrospectively analyzed up to four years pre- and post-diagnosis. These specimens were sent to the German Cancer Research Center (DKFZ, Heidelberg, Germany) for analysis of antibodies against the early oncoproteins of carcinogenic mucosal HPV types, particularly HPV16 and other high-risk HPVs. Results: One hundred thirty-seven patients living with HIV (PWH) were included in the analysis. The distribution of PWH diagnosed with oropharyngeal cancer, anal cancer, aHSIL, and aLSIL was 6, 14, 96, and 9 respectively. Regarding HPV16 E6 seropositivity, 100% of patients with oropharyngeal cancer tested positive (6/6). Seropositivity rates for anal cancer, aHSIL, and aLSIL were 28.6% (4/14), 12.5% (12/96), and 11.1% (1/9) respectively (Table). Patients with oropharyngeal cancer exhibited the highest titer of HPV16 E6. Among the six patients with oropharyngeal cancer, one demonstrated persistent positivity from four years prior, and four showed positivity from one year prior. Two patients were not assessed as they were newly diagnosed at the time of the study. After chemoradiation treatment, their titers decreased but did not fall below the cutoff level during the follow-up period. In two cases of relapse, the titers, which had initially decreased with chemoradiation, increased again at least one year before the relapse diagnosis. Conclusions: The study demonstrated that screening for HPV16 E6 seropositivity is highly effective for the detection of oropharyngeal cancer in HIV-MSM. This could potentially contribute to early diagnosis and treatment of HPV-related cancers. [Table: see text]