bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer risk associated with missense variants in BRCA2.
Authors: Yadav Siddhartha , Richardson Marcy , Karam Rachid , Boddicker Nicholas J. , Hu Chunling , Tecleab Yohannes A , Kraft Peter , Weitzel Jeffrey N. , Domchek Susan M. , Nathanson Katherine , Couch Fergus 
Published: June 2023

10501 Background: Greater than 90% of missense variants in BRCA2 are classified as variants of uncertain significance (VUS). In addition, among the few known missense pathogenic variants (PVs) in BRCA2, breast cancer risk has been reported to be lower compared to pathogenic truncating variants (PTVs) (Li et al., 2022) . Herein, we aim to reclassify several missense variants in BRCA2 and investigate the associated breast cancer risk. Methods: A total of 450 BRCA2 missense variants in the C-terminal DNA binding domain (DBD) were evaluated for functional effect utilizing a previously validated homology-directed DNA double-strand repair (HDR) assay. The results of the functional evaluation along with clinical, structural, and in-silico data were applied to the rules-based ACMG/AMP criteria for variant classification to identify pathogenic/likely pathogenic (P/LP) variants and benign/likely benign (B/LB) variants. A pooled case-control analysis was performed comparing the frequency of reclassified P/LP missense variants among 82,372 women with breast cancer within the Ambry Genetics database as cases and 174,167 unaffected women within gnomAD, CARRIERS, and BRIDGES datasets as controls to evaluate associated breast cancer risk. Separate case-control analysis and comparisons with BRCA2 DBD PTVs, exon 11 PTVs, and known missense PV standards in ENIGMA were also performed. Results: From the 450 missense variants in the DBD, 137 (30.4%) were noted to be functionally deleterious and 313 (69.6%) were functionally neutral by the HDR assay. Incorporation of the functional and other data into an ACMG/AMP model led to the reclassification of 439 (97.6%) variants, with 131 as P/LP and 308 as B/LB variants. In a pooled case-control analysis, reclassified BRCA2 missense P/LP variants were associated with clinically significant increased risks of breast cancer (Odds Ratio (OR):5.6, 95%CI:3.9–8.0), whereas B/LB missense variants were not (OR:1.1, 95%CI:1.1–1.2). Similarly elevated risks of breast cancer were observed for BRCA2 PTVs in the DBD (OR:6.8, 95%CI:5.1–9.0) and missense PV standards in ENIGMA (OR:7.8, 95%CI:4.1–14.7). However, PTVs in exon 11 of BRCA2 were associated with a lower risk of breast cancer (OR:4.4, 95%CI:3.8–4.9) compared to PTVs in DBD, confirming the ovarian cancer cluster region effect in BRCA2. Conclusions: The study demonstrates that the HDR functional assay in conjunction with other clinical and genomic data can be a powerful tool that can aid in the reclassification of > 95% of missense variants in BRCA2. In addition, missense PVs in DBD were noted to have a similarly elevated risk of breast cancer as PTVs. The reclassification of the BRCA2 missense VUS and identification of associated breast cancer risk in this study will significantly influence breast cancer risk assessment and management strategies among carriers of these missense variants.
Polygenic risk score calibration and association with breast cancer in diverse ancestries.
Authors: Kucera Matthew , Hughes Elisha , Mabey Brent , Hullinger Brooke , Pederson Holly Jane , Pal Tuya , Domchek Susan M. , Eng Charis , Garber Judy Ellen , Gordon Ora , Klemp Jennifer R. , Mukherjee Semanti , Vijai Joseph , Pruthi Sandhya , Kurian Allison W. , Whitworth Pat W. , Lanchbury Jerry , Slavin Thomas Paul , Gutin Alexander , Olopade Olufunmilayo I. 
Published: June 2023

10505 Background: Polygenic risk scores (PRS) have been shown to substantially improve breast cancer (BC) risk prediction when incorporated into traditional risk assessment models. However, PRS developed primarily in women of European ancestry have shown poor performance when applied to non-European populations. We previously described development and validation of a multiple-ancestry PRS (MA-PRS) that is based on individual ancestral genetic composition. MA-PRS has been incorporated into the Tyrer-Cuzick model for use in clinical practice and has been shown to provide independent value to the model. Here, we describe performance of the MA-PRS in a large cohort of women from diverse ancestral backgrounds. Methods: The study cohort included 203,586 patients who were referred for hereditary cancer testing and negative for pathogenic variants in genes associated with BC. MA-PRS was calculated as previously described based on 149 SNPs (93 BC and 56 ancestry-informative). Association of MA-PRS with invasive BC status (affected vs unaffected) was analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Calibration was assessed by examining the MA-PRS distribution within unaffected patients, and through goodness-of-fit tests. All analyses were conducted within the full cohort and within ancestral subpopulations. Odds ratios (ORs) are reported per standard deviation. Results: One-fifth (43,782/203,586, 21.5%) of patients were diagnosed with invasive BC, and 60,657 (29.8%) of patients reported BC in a first degree relative. The MA-PRS distribution was centered around zero among unaffected patients overall and within each subpopulation. MA-PRS significantly improved BC risk prediction over clinical factors in the full cohort (OR = 1.43, 95% CI:1.41-1.44) and within each ancestral subpopulation (Table). The strongest associations were observed in Ashkenazi Jewish (OR = 1.56, 95% CI:1.39-1.76) and South Asian (OR = 1.49,95% CI: 1.23-1.81) populations. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. Conclusions: The breast cancer MA-PRS based on genetic ancestral composition is well-calibrated and strongly associated with BC in all tested ancestral populations. Incorporation of PRS adds independent information to risk models and supports equitable access to personalized BC risk management. [Table: see text]
Whole exome sequencing and machine learning germline analysis of individuals presenting with phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma.
Authors: Perez-Gracia Jose Luis , Guruceaga Elisabet , Andueza Maria Pilar , Ocon Marimar , de VIllalonga Zornoza Nicolas , Fodop Sokoudjou Jafait Junior , Alkorta-Aranburu Gorka , Camps Carlos , Jantus-Lewintre Eloisa , Navamuel Andueza Maria , Sanmamed Miguel F. , Gurpide Alfonso , Melero Bermejo Ignacio , Elgendy Mohamed , Perez Valencia Juan Alberto , Hernaez Mikel , Pio Oses Ruben , Montuenga Luis M. , Ochoa Idoia , Patiño-García Ana 
Published: June 2023

10507 Background: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at young age others never develop it, even at advanced age. This suggests a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at early age ( extreme cases) or did not develop it at advanced age ( extreme controls). The discovery and validation cohorts included respectively 50 and 66 extreme cases and 50 and 83 extreme controls, selected from databases including > 6,000 subjects. We selected individual coding variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We trained ML models (Logistic Regression, Random Forest, Support Vector machine Classifier (SVC)) on the discovery cohort to classify subjects into their respective phenotypes and tested them on the validation cohort. Results: Mean age for extreme cases and controls in both cohorts was 50.2 and 78.4 years. Mean tobacco consumption was 38.1 and 59.1 pack-years. We validated 16 significant individual variants. The most significant variants were in ADAMTS7 (2 variants) in cases and TMEM191B (1) in controls. We validated 33 genes enriched with significant variants. The genes harboring more variants were HLA-A (4 variants) and ADAMTS7 (2) in cases; and PLIN4 (2) in controls (Table). We trained several ML models on the discovery cohort using as input the 16 significant individual variants and the number of variants in the 33 enriched genes. We tested them in the validation cohort obtaining accuracy of 72% and AUC-ROC of 87.4% with the best model (SVC), using 16 variants as input, confirming their association with the phenotypes. Functions of validated genes included oncogenes, tumor-suppressors, DNA repair, maintenance of genomic stability, HLA mediated antigen presentation and regulation of proliferation, migration, apoptosis and inflammatory pathways. Conclusions: Individuals presenting phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma have different germline profiles. Our strategy may allow to identify high-risk subjects and to develop new therapeutic approaches. [Table: see text]
Clinical evaluation of cancer signal origin prediction and diagnostic resolution following multi-cancer early detection testing.
Authors: Klein Eric A. , McDonnell Charles H. , Nadauld Lincoln , Dilaveri Christina A. , Reid Robert Lawrence , Marinac Catherine R. , Chung Karen C. , Lopatin Margarita , Fung Eric T. , Schrag Deborah , Shaknovich Rita 
Published: June 2023

10520 Background: PATHFINDER (NCT04241796) was a prospective, interventional return of results study that enrolled 6,662 participants (pts) from 7 US institutions to assess clinical implementation of a blood-based multi-cancer early detection (MCED) test. Test results for those with a cancer signal detected also included a cancer signal origin prediction designed to help guide diagnostic evaluations. We analyzed whether the diagnostic evaluations in PATHFINDER were appropriately directed by cancer signal origin predictions, assessed the residual risk of cancer after negative initial evaluation, and examined the role of whole-body imaging (WBI, defined as PET/CT or CT chest/abdomen/pelvis) in diagnostic evaluation. Methods: Analysis included pts with a cancer signal detected result from the two different versions of an MCED test evaluated in PATHFINDER. Prespecified criteria blinded to study results were used to define expected diagnostic evaluations by cancer signal origin prediction. These criteria were then used to judge concordance between cancer signal origin predictions and the diagnostic evaluation actually performed. Definitive cancer or no cancer diagnosis (cancer status at end of study [EOS]) was assessed at 12 months after enrollment (EOS). Results: 39 pts had cancer signal detected results by both test versions. Diagnostic evaluations were consistent with cancer signal origin in 30/39 (77%) cases. Diagnostic resolution was achieved in 32/39 (82%) pts after initial evaluation, while 7/39 (18%) required additional workup. 25 of the 32 (78%) pts who achieved diagnostic resolution after initial evaluation had a cancer signal origin-guided workup. Additional evaluation of the 7 pts not achieving initial diagnostic resolution was based on persistent clinical suspicion of cancer due to prior cancer history (n = 1) or abnormal/equivocal findings on initial evaluation (n = 6). Additional workup led to diagnostic resolution in all 7 cases (3 with cancer and 4 with no cancer confirmed at EOS). WBI was ordered in 27 cases, of whom 9 had a prior cancer history, 10 had non-localizing cancer signal origin (hematologic or indeterminate), and 1 had both. WBI was equivocal or had no impact on diagnostic resolution in 8/27 (30%) cases. Conclusions: Most cases resulted in diagnostic resolution after cancer signal origin-directed diagnostic workup. In pts with a cancer history and negative initial evaluations, and those with equivocal initial evaluations, there was still a risk of cancer, suggesting the need for additional evaluation. WBI was used mostly in those with a cancer history or non-localizing cancer signal origins, and had no impact on diagnosis in almost one-third of pts. Clinical trial information: NCT04241796 .
CDH1 incidental findings in patients with personal or family history of breast cancer.
Authors: Abdel-Salam Hiam , Mansfield Paul F. , Moskowitz Julie B , Arun Banu 
Published: June 2023

10524 Background: Pathogenic variants in CDH1 ( CDH1+) are associated with hereditary diffuse gastric cancer (HDGC), with an increased risk for DGC (~40-83%) and lobular breast cancer (BC) (~64%) [1]. The National Cancer Center Network recommends the inclusion of CDH1 in multi-gene panel testing (MGPT) for patients with significant history of BC, given its classification as a high-risk BC gene [2]. Management includes prophylactic gastrectomy or consideration of annual endoscopic biopsies and high-risk breast screening, with consideration of prophylactic mastectomy. Several studies have identified CD H1+ patients who do not meet the International Gastric Linkage Consortium’s diagnostic criteria for HDGC [3.4,5,6]. These studies have brought concerns of CDH1 pathogenic variants in patients with low risk phenotypes, given the potential for total gastrectomy to reduce DGC risk. Our study aims to investigate our cohort of patients with a personal and/or family history of BC to determine if there is a significant number of CDH1+ patients with a non-classical presentation of HDGC. Methods: 17,208 families with a history of BC who underwent MGPT were seen in a Clinical Cancer Genetics (CCG) high-risk breast clinic between August 2013 and July 2022. They were identified using a prospectively maintained MD Anderson Cancer Center CCG database. Families were categorized by their history of GC and CDH1 status. Results: Among the families, 10,202 (59%) had a proband with a personal history of BC, with a mean age of onset of 51 years. 49 families (0.28%) were CDH1+. 21 CDH1+ families (43%) had no personal and/or family history of GC. Overall, 0.12% of families within the cohort were CDH1+ and had no family history of GC. A chi-square goodness of fit test was performed comparing observed (O) versus expected frequencies (E) (O/E) of families that were: 1) CDH1+ and had a history of GC (28/28), 2) CDH1+ and no history of GC (21/21), 3) CDH1 – (benign variant or variant of unknown significance (VUS)) and a history of GC (180/164), and 4) CDH1- and no history of GC (16,979/16,995). O was determined by using a general population risk of GC (0.81%) and estimated risk of DGC for CDH1+ individuals (58.2%). The X2 was determined to be 1.576, with a p-value of 0.66483. Conclusions: In comparison to the expected frequency of incidental CDH1+ families identified via MGPT, we found that there was not a significant difference in expected and observed frequencies of families based on CDH1 status and presence of GC. These results likely reflect the incomplete penetrance and variable expressivity of HDGC, in addition to reported cases of occult signet ring cell carcinomas in biopsy samples or surgical pathology that has been reported in low risk presenting families [7]. We seek to validate these results with cohort of patients in which the diffuse gastric cancer pathology is known and to expand the analysis in patients specifically with a personal history of lobular breast cancer.
Trends in diagnosis of de novo metastatic hormone sensitive prostate cancer in US Veterans, 2002-2021.
Authors: Al masalmeh Nada , Etzioni Ruth Douglas , Khan Saira , Babar Arslan , Sanfilippo Kristen Marie , Montgomery Robert Bruce , Knoche Eric Marshall , Owens Lukas , Wong Yu-Ning , Schoen Martin W. 
Published: June 2023

10527 Background: The incidence of non-localized prostate cancer in the US has been increasing since 2011. While the etiology of this increase is unknown, improved detection of metastatic disease and changes in prostate-specific antigen (PSA) screening may be contributing factors. In this retrospective study, we report the frequency and characteristics of veterans with de novo metastatic prostate cancer to understand changes in the diagnosis over time. Methods: The study population consisted of veterans diagnosed with de novo metastatic Hormone Sensitive Prostate Cancer (mHSPC) with a biopsy between 2002 and 2021 in the Veterans Health Affairs Prostate Cancer Data Core were included. All patients had no prior diagnosis of prostate cancer and were classified as SEER stage ‘distant’. We collected the highest PSA within 3 months of diagnosis, age, race, and calculated the Charlson Comorbidity Index. Year of diagnosis was categorized into 5-year periods and differences over tine were assessed by chi-square linear by linear ANOVA test for linearity as appropriate. Results: 15,485 patients were diagnosed with de novo mHSPC between 2002 and 2021. The mean age was 72.9 years and the median PSA was 88.0 ng/mL. There was a 39% increase of the number of patients diagnosed with mHSPC (from 3,274 between 2002-2006 to 4,560 between 2017-2021). Mean age increased from 71.6 years between 2002-2006 to 74.4 between 2017-2021 (p < 0.001). Median PSA decreased from 96.6 ng/mL in 2002-2006 to 80.3 ng/mL in 2006-2021 (p < 0.001). The percentage of patients who were identified as black decreased from 29.8% between 2002-2006 to 25.4% between 2017 and 2021 (p < 0.001). Mean comorbidity index increased from 3.2 between 2002-2006 to 4.5 between 2017-2021 (p < 0.001). BMI increased from 26.2 between 2002-2006 to 27.2 between 2017-2021 (p < 0.001). Median overall survival improved from 26.7 months in 2002-2006 to 31.7 months in 2016-2021 (p < 0.001). Conclusions: Over a 20-year period, the Veterans diagnosed with prostate cancer were older, with higher comorbidities and with decreased PSA at diagnosis. Additionally, overall survival improved from 26.7 to 31.7 months. The findings of this study are consistent with a reduction in screening and more sensitive imaging modalities to detect metastatic disease combined with changes in the veteran population and improvements in treatment of mHSPC. Further study is warranted to understand these trends over the same time period. [Table: see text]
Breast cancer: Global patterns of incidence, mortality, and trends.
Authors: Sedeta Ephrem Tadele , Jobre Bilain , Avezbakiyev Boris 
Published: June 2023

10528 Background: The global burden of cancer incidence and mortality including that of female breast cancer continues to increase largely because of the growth and aging of the population and adoption of western lifestyle behaviors that increase cancer risk. In this study, we summarize the current burden, trends, and survivorship of female breast cancer that account for nearly 12% of the cancer burden worldwide. Methods: Estimates of incidence and mortality in the year 2020 were obtained from Global Cancer Observatory (GLOBOCAN) database. GLOBOCAN provides country-specific estimates of cancer incidence, mortality, and prevalence for 185 countries or territories and 36 cancer types by age group and sex. For US rates, data from Surveillance, Epidemiology, and End Results (SEER) program were assessed. Rates are age-standardized (ASRs) (per 100,000 person-years) using the 1966 Segi-Doll World Standard Population. Geographic variability was assessed using 20 predefined world regions, and the 4-tier Human Development Index (HDI). Finally, we provide a prediction of the future burden of female breast cancer in 2040 based on demographic projections. Results: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, with an estimated 2.3 million new cancer cases (1 in 4 new cancer cases) and 685,000 cancer deaths (1 in 6 deaths) in 2020. Breast cancer incidence rates varied by nearly 4-fold across WHO areas. The highest incidence rates (per 100,000) were found in Australia/New Zealand (95.5), Western Europe (90.7), and Northern America (89.4), while the lowest rates were in South-Central Asia (26.2), Middle and Eastern Africa (33), and Central America (39.5). In contrast, the highest breast cancer mortality rates were recorded in Melanesia (37.5), Polynesia and Western Africa (22.3), and the Caribbean (18.9), while the lowest rates were found in Eastern Asia (9.8), Central America (10.4), and Australia/New Zealand (12.1), a 2.8-fold difference. In the United States, the age-standardized breast cancer incidence rate (per 100,000) increased from 106 (1975) to 142 (1999), decreased to 128 (2004), and then slowly increased to 137 (per 100,000) in 2019. Similar broad temporal trend patterns were observed in other western countries. Incidence rates are rising in South America, Africa, and Asia where rates were historically low. Worldwide, an estimated 2,964,197 new female breast cancer cases are projected to occur in 2040, a 31% increase from the corresponding 2,260,127 cases in 2020. Conclusions: There is significant variation in female breast cancer incidence and mortality rates worldwide. Breast cancer incidence is increasing at different rates in various regions of the world. Mortality rates in many high HDI countries have been on the decline, in contrast to increasing rates in low HDI countries. This study also shows a substantial increase in new breast cancer diagnoses over the next two decades.