bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redefining early-onset cancer and risk of hereditary cancer predisposition.
Authors: Stadler Zsofia Kinga , Maio Anna , Khurram Aliya , Kemel Yelena , Padunan Angelika , Borio Matilde , Sheehan Margaret , Murciano-Goroff Yonina R. , Walsh Michael Francis , Will Marie , Liu Ying L , Carlo Maria Isabel , Latham Alicia , Glade Bender Julia Lynne , Cercek Andrea , Tap William D. , Solit David B. , Mandelker Diana , Offit Kenneth , Diaz Luis A. 
Published: June 2023

10510 Background: For most solid tumors, early age of onset, a marker for potential increased inherited risk, has been arbitrarily defined as a diagnosis of cancer at age < 50. However, this disregards the variation in mean age of diagnoses across solid tumors resulting in the potential misclassification of patients at increased risk of germline alterations. Methods: 25,305 prospectively ascertained cancer patients, representing 32 solid tumor types, underwent sequencing analysis of up to 90 cancer predisposition genes using next-generation genetic analysis with reporting of germline likely pathogenic (LP) and pathogenic variants (P). Mean age of diagnosis by cancer type, with standard deviations (STD), were calculated according to Surveillance, Epidemiology, and End Results Program (SEER) data. Early-onset (EO-CA), average-onset (AO-CA), and late-onset (LO-CA) cancers were defined as cancers diagnosed < -1 STD, -1 < STD > 1, and > 1 STD around the mean age at diagnosis for the specific cancer type, respectively. Prevalence of LP/P variants was classified according to age of onset. Statistical analyses were performed using STATA. Results: Among 25,305 patients with 32 solid tumor types classified as per SEER data, 31% (n = 7,854) of patients were categorized as having EO-CA. Overall prevalence of germline alterations varied as a function of age at diagnosis with 19.2%(n = 1509), 15.9% (n = 2588/16,299), and 12.9% (149/1152) of EO-CA, AO-CA, and LO-CA patients harboring a germline LP/P variant (p < 0.0001). The enrichment of variants in EO-CAs was driven by high- and moderate-penetrance genes with 13.2%, 9.2% and 5.1% of EO-CA, AO-CA, and LO-CA patients having an LP/P variant (p < 0.0001); low-penetrance germline alterations were static across the age groups (6%, 6.7%, 7.8%). An age cutoff of 50 for early-onset cancer was > 1 STD below the mean age at diagnosis in 20 cancer types resulting in 2,226 patients who would not have been classified as having EO-CA inclusive of 394 patients who tested positive for a germline LP/P, representing 26.1% of all germline EO-CA positives. Conclusions: Early-onset cancer should be defined taking into consideration the mean age at diagnosis for a specific cancer type as an arbitrary cutoff of age < 50 misses over 25% of patients with an inherited cancer predisposition syndrome. Due to the high prevalence of inherited predisposition syndromes, genetic testing of all patients with EO-CA, irrespective of tumor type, is warranted.
Real-world performance of a multi-cancer early detection test based on integrative analysis of cell-free DNA whole-methylome sequencing.
Authors: LI Yulong , Song Xiaofeng , Shen Ning , Hong Yuanyuan , Yang Ying , Huang Yu S. , Chen Weizhi 
Published: June 2023

10521 Background: Early detection and diagnosis is key to reducing cancer-related mortality. We developed a blood-based multi-cancer early detection test, called THEMIS, using multimodal analysis of plasma cell-free DNA (cfDNA) methylation, fragmentation, and copy number alteration features by whole-methylome sequencing (WMS). The real-world performance of THEMIS was investigated with a prospective cohort of high-risk populations and the preliminary results were reported here. Methods: A total of 1,374 adults over 65 y with additional cancer risk factors for five common cancers (colorectal, esophageal, liver, lung, or stomach cancer) were recruited in the city of Wuxi, Jiangsu province, China. Additional risk factors included fecal occult blood, smoking history, H. pylori infection, HBV infection, and serum protein biomarkers. Participants had no known cancer diagnosis at the time of administration. Blood samples were collected and subject to low-pass WMS assay (~2X) and cancer probability was predicted by the THEMIS model, which was developed and locked in previous studies. Participants predicted as cancer positive by THEMIS were followed up until positive cancer diagnosis in a clinic or one year after receiving the test report, whichever was earlier. Results: At a fixed cutoff rendering 99% training specificity, THEMIS predicted 58 (4.15%) positive cases, among whom 19 participants consented to and completed follow-up. Ten participants received confirmed cancer diagnosis within the follow-up period, including five lung cancers, three liver cancers, one esophageal cancer, and one colorectal cancer. These results yielded a positive predictive value (PPV) of 52.6%. Those who declined follow-up upon a positive THEMIS report were predicted with digestive tract cancers, which need gastrointestinal endoscope for diagnostic confirmation. Conclusions: The nonivasive blood-based THEMIS test demonstrated promising performance and patient compliance for clinical utility to detect cancer early and improve patient outcome. Given that clinical follow-ups were only conducted with a subset of participants, future investigations of the precise real-world performance of THEMIS are needed with more complete patient follow-up.
Germline mutations and the presence of clonal hematopoiesis of indeterminate potential (CHIP) in 20,963 patients with BRCA-associated cancers.
Authors: Marshall Catherine Handy , Gondek Lukasz , Mauer Elizabeth , Chao Calvin Y. , Luo Jun , Antonarakis Emmanuel S. 
Published: June 2023

10522 Background: The contribution of germline genetics on the emergence of CHIP in patients with solid tumor malignancies is not well understood. We hypothesized that those with germline (g) alterations in homologous recombination repair genes (gHRR) and BRCA-associated cancers (breast, ovarian, prostate, pancreas) would have different rates of CHIP than those without. Methods: We analyzed a large real-world Tempus multimodal database of paired germline and somatic DNA sequencing results. CHIP was calculated based on the presence of pathogenic or likely pathogenic alterations in any one of 16 CHIP-associated genes ( ASXL1, BCOR, BCORL1, CBL, CREBBP, CUX1, DNMT3A, GNB1, JAK2, PPM1D, PRPF8, SETDB1, SF3B1, SRSF2, TET2, U2AF1) with a variant allele frequency of at least 2%. Patients with g alterations in BRCA1, BRCA2, ATM, CHEK2, and PALB2 were compared to those without gHRR alterations (sporadic). Results: In breast cancer, patients with g BRCA1 (n = 104) mutations were younger (med 43 yrs) at diagnosis compared to sporadic cases (n = 6,546 med 56yrs) but had similar rates of CHIP (3% vs 5%). Those with gPALB2 (n = 42 med age 55) had the highest rate of CHIP (14%). gBRCA2 (n = 148; med age 52), gATM (n = 57 med age 52), and gCHEK2 (n = 57 med age 53) and similar rates of CHIP (3%, 4%, 7%). In ovarian cancer, patients with gBRCA1 (n = 137 med age 53) were younger at diagnosis than sporadic cases (n = 3,979 med age 63) with similar rates of CHIP (4% vs 3%). Those with gBRCA2 (n = 83 med age 61) were similar (4%) and gPALB2 (n = 11 med age 68) had the highest rate of 9%. CHIP was not detected among patients with g ATM (n = 23 med age 61) or g CHEK2 mutations (n = 9, med age 59). In prostate cancer, 4% of patients with sporadic cases had CHIP (n = 4,183 med age 66) compared to 4% in gBRCA2 (n = 109 med age 63) and 5% in gATM (n = 44 med age 66). gCHEK2 had 17% prevalence of CHIP (n = 12 med age 66) followed by gPALB2 (n = 12 med age 69). There were no CHIP mutations found among those with g BRCA1 (n = 16 med age 64). In pancreatic cancer, patients with g BRCA2 (n = 89 med age 64) and PALB2 (n = 20 med age 62) were younger at diagnosis, compared to sporadic cases (n = 5,176 med age 67) with lower rates of CHIP (1% gBRCA2, 0 PALB2, 5% sporadic). The highest proportion was in gBRCA1 patients (n = 20 med age 63) with 10%, gCHEK2 (n = 16 med age 68) with 6% and gATM (n = 60 med age 66) with 5%. Conclusions: Despite younger age at diagnosis, patients with g BRCA1 had similar or higher rates of CHIP within breast and ovarian cancer. Women with g PALB2 alterations and breast and ovarian cancer, as well as men with g CHEK2 mutations and prostate cancer, had higher rates of CHIP. These data suggest that gHRR mutations may influence the prevalence of CHIP among patients with BRCA-associated cancers and more research is needed.
Twenty-year patterns in area deprivation index and risk of metastatic prostate cancer at initial diagnosis among men in Ohio.
Authors: Cullen Jennifer , Payne Julia Yang , Rhodes Stephen Paul , Shoag Jonathan Evan 
Published: June 2023

10526 Background: Men diagnosed with prostate cancer (PCa) have a 5-year overall survival (OS) rate of 98%. However, this rate plummets to approximately 30% for men diagnosed with metastatic PCa. Furthermore, PCa exerts a greater burden on African American men with a higher incidence and a higher mortality rate than other races. These disparities have been contributed to a result of interactions among genes, health behaviors, and access to care. In our study, we examined Social Determinants of Health (SDoH) – social risk factors that contribute to disparities in cancer mortality. Area deprivation index (ADI) is one of the assessments used to measure these social risk factors. ADI can assess a geographic area’s level of socioeconomic deprivation and is associated with health outcomes on the census block level. Variables used in ADI are grouped into 4 domains – education, income, employment, and housing quality. Most of the communities will fall between a standardized score of 40 to 160. In this study, we used a large population-based cancer database to examine the impact of ADI on risk of metastatic PCa at diagnosis in Ohio. Methods: The Ohio Cancer Incidence Surveillance System (OCISS) data were examined for the period 1996 to 2016 to predict the odds of distant stage at diagnosis. Generalized additive models were constructed with age and year of cancer diagnosis, area deprivation index, race, and Hispanic ethnicity as predictors. The relationship between continuous variables and odds of distant diagnosis was modeled via penalized cubic splines. Odds ratios were calculated for race and Hispanic ethnicity. To summarize the results for variables modeled via splines, predicted probabilities were calculated with other variables held at their average or reference values. Results: We identified 112,023 men with PCa in OCISS database. The median age was 67 (IQR 61-67) years old. Subjects were 85.3% White, 13.8% Black, and 0.9% other races. Only 0.6% of men were Hispanic. By stage, 84.6% (N=94753) had localized PCa, 10.4% (N=11640) had regional PCa, and 5.0% (N=5571) had distant PCa. The median ADI was 93.9 (IQR 83.6-106.5). Our analysis showed that Black men had 41.8% higher odds of having metastatic PCa at diagnosis than White men. Furthermore, our analysis showed similar risk of metastatic PCa at diagnosis in lower ADI values but higher risk at higher ADI values (Table). Conclusions: Higher ADI values were associated with higher risk of metastatic PCa at diagnosis. Interventions should target populations with socioeconomic deprivation and aim to improve patient access to prostate cancer prevention, screening, and treatment services. [Table: see text]
Examining the potential for lead-time bias by estimating stage-specific proportions of deaths due to diagnosed cancer.
Authors: Chang Ellen T. , Clarke Christina A. , Colditz Graham A. , Gomez Scarlett L. , Kurian Allison W. , Hubbell Earl A. 
Published: June 2023

10535 Background: Lead-time bias occurs when cancer is detected earlier in time, but with no change in lifespan. Cause of death is not susceptible to lead-time bias; therefore, stratifying cause of death by cancer stage informs the potential for lead-time bias in early detection across cancer types. Methods: Using recent data from 17 US Surveillance, Epidemiology, and End Results (SEER) cancer registries for 1 152 610 first incident primary cancers among patients aged 50–84 years at diagnosis in 2006–2010, we evaluated proportional causes of death by cancer type and uniformly classified stage at diagnosis (American Joint Committee on Cancer, 6th edition), following or extrapolating all patients until death. Results: A minority of cancer patients diagnosed at stages I–II (27%) went on to die from their index cancer, whereas most stage IV cancer patients (85%) did. For patients diagnosed with stage I cancer at all sites combined, an estimated 26% of deaths were due to the index cancer, 61% due to non-cancer causes, and 12% due to a subsequent primary (non-index) cancer. At stage II, 27% of deaths were due to the index cancer, 60% due to non-cancer causes, and 13% due to a non-index cancer. In contrast, at stage IV, 85% of deaths were attributed to the index cancer, with 13% non-cancer and 2% non-index-cancer deaths. Index cancer mortality from stages I–II cancer was proportionally lowest for thyroid, melanoma, uterus, prostate, and breast, and highest for pancreas, liver, esophagus, lung, and stomach. Leading causes of non-index cancer death (lung, pancreas, and colorectal) and non-cancer death (heart disease and COPD) at each stage were similar to those in the general US population. Non-White racial/ethnic groups, including Hispanics and non-Hispanic Blacks, Asian Americans/Pacific Islanders, and American Indians/Alaska Natives, experienced a higher percentage of deaths from stages I–II cancer than non-Hispanic Whites. Conclusions: Across all cancer types, the percentage of patients who went on to die from their cancer was three times greater at stage IV than at stages I–II. As mortality patterns are not influenced by lead-time bias, these data suggest that earlier stage at diagnosis is broadly, if not uniformly, associated with substantially reduced risk of cause-specific death from cancer; therefore, early detection is likely to improve outcomes across cancer types, including those currently unscreened. [Table: see text]
Incomplete HPV vaccination among individuals aged 27-45 years in the United States: A mixed effect analysis of individual and contextual factors.
Authors: Adekanmbi Victor , Guo Fangjian , Hsu Christine , Kuo Yong-Fang , Berenson Abbey 
Published: June 2023

10546 Background: In the United States, the Human papillomavirus (HPV) vaccine is approved for use up to age 45. Incomplete HPV vaccination rates among those over age 26, however, remain high. The aim of this study was to examine the independent effects of individual- and neighborhood-level factors on incomplete HPV vaccine series in the United States (US) among those aged 27-45 years. Methods: This retrospective cohort study used administrative data from Optum’s Clinformatics DataMart Database to identify individuals aged 27-45 years who received 1 or more doses of HPV vaccine between July 2019 and June 2022. Multilevel multivariable logistic regression models were applied to the data on 7,662 individuals aged 27-45 years who were fully vaccinated against HPV or not, nested within 3839 neighborhoods across the US. Results: More than half of the participants in this study (52.93%) were not completely vaccinated against HPV. About 64% of the eligible participants aged 27-30 years did not complete their HPV vaccine series. After adjusting for all other covariates in the final model, being older than 30 years old decreased the odds of incomplete HPV vaccine series. Participants living in neighborhoods of South region of the US had enhanced odds of incomplete HPV vaccine series compared to those residing in Northeast region (aOR 1.21; 95% CrI 1.03–1.42). There was significant clustering of incomplete HPV vaccine series at the neighborhood level. Conclusions: This study revealed that individual- and neighborhood-level factors significantly influence HPV vaccination incompleteness in the US. Interventions to improve HPV vaccination uptake and completion should take into consideration both individual- and contextual-level characteristics during design, planning and implementation of policies and programs to improve HPV vaccination coverage and completion in the US and other similar countries. Acknowledgement Dr. Adekanmbi is supported by a research career development award (K12HD052023: Building Interdisciplinary Research Careers in Women’s Health Program-BIRCWH; Berenson, PI) from the National Institutes of Health/Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD). Dr. Guo is currently supported by an award (K07CA222343) from the National Institutes of Health, National Cancer Institute (NIH/NCI). Dr. Berenson is supported by an award (PP200048) from the Cancer Prevention and Research Institute of Texas (CPRIT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CPRIT. Conflict of Interest: All authors report no conflicts of interest.
Sex differences in cancer incidence rates by race and ethnicity: Results from the surveillance, epidemiology, and end results (SEER) Registry (2000-2019).
Authors: Tosakoon Sararat , Lawrence Wayne R. , Shiels Meredith S. , Jackson Sarah S. 
Published: June 2023

10547 Background: Sex differences in cancer incidence are pronounced, with men having 2-3 times the rate of most non-reproductive cancers than women. However, whether the male predominance is due to differences in biological factors or behavior remains not well understood. This study investigated sex differences in cancer incidence by race and ethnicity to provide a greater understanding of whether differences are driven by biological factors or environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology and End Result (SEER) program (2000-2019) was used to calculate male-to-female incidence rate ratios (MF IRR) for each cancer site and histological subtype, stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic), and age-standardized to the 2000 U.S. population for individuals ages ≥20 years. Results: Most non-reproductive cancers had a male predominance across race and ethnicity, with the largest MF IRR seen for cancers of the tonsil, hypopharynx, larynx, and Kaposi sarcoma (MF IRR > 4). Three cancers, gallbladder; peritoneum, omentum, mesenter; and thyroid, were more common among females than males across all race and ethnicity. Females had a higher incidence of anal cancer than males for all racial and ethnic groups except for non-Hispanic Black individuals where the MF IRR was >1. Cancers of the stomach, skin (excluding basal and squamous cell), melanoma skin, and other non-epithelial, and myeloma had greater MF IRR among non-Hispanic White adults than all other racial and ethnic groups. Non-Hispanic Black individuals had higher MF IRR of cancers of the liver and lung and bronchus, compared to other racial and ethnic group. Non-Hispanic White males had the highest MF IRRs for esophagus adenocarcinoma and gastric cardia adenocarcinoma and the lowest MF IRR for esophagus SCC compared to other races and ethnicity. Conclusions: The MF IRR for most cancers in this study did not differ by race and ethnicity, suggesting the influence of biological factors. Differences in the MF IRR across race and ethnicity may indicate carcinogenic exposure differences leading to the development of non-sex-specific cancers. Further research is needed to identify biological drivers of cancer incidence for most non-reproductive cancers. Funding: Intramural Research Program of the Division of Cancer Epidemiology and Genetics in the National Cancer Institute, National Institutes of Health.
Polygenic risk scores in assessing lung cancer susceptibility in non-Hispanic White and Black populations.
Authors: Trendowski Matthew R , Lusk Chrissy , Wenzlaff Angie , Neslund-Dudas Christine , Gadgeel Shirish M. , Soubani Ayman , Schwartz Ann G. 
Published: June 2023

10548 Background: Polygenic risk scores (PRS) have become an increasingly popular approach to evaluate cancer susceptibility, but have not adequately represented Black patients in model development. We used previously identified single nucleotide polymorphisms (SNPs) and annotated SNPs in associated gene regions to develop PRS in non-Hispanic Whites and Blacks using the INHALE dataset. Methods: Using the Multi-Ethnic Genotype Array, 1,204 SNPs for non-Hispanic Whites and 1,515 SNPs for Blacks were evaluated for their association with lung cancer risk adjusting for age, sex, total pack-years, family history of lung cancer, history of COPD and the top five PCs for genetic ancestry. Gene region-specific significant SNPs (p < 0.05) were used to develop race-specific PRS. Results: The race-specific PRS included different sets of significant SNPs and were highly associated with lung cancer risk in both non-Hispanic Whites (OR = 1.07, 95% CI: 1.05-1.09, p = 3.44x10-9) and Blacks (OR = 1.12, 95% CI: 1.08-1.17, p = 9.14x10-8). These models remained significant for both Whites (OR = 1.05, 95% CI: 1.03-1.09, p = 0.0004) and Blacks (OR = 1.08, 95% CI: 1.01-1.15, p = 0.01) who currently do not meet USPSTF screening guidelines. AUC analysis demonstrated the Black-specific model (AUC = 0.68) outperformed the White-specific model (AUC = 0.57) (p = 0.03) when examined exclusively in the Black cohort. Conclusions: Using previously validated SNPs and gene regions, we developed race-specific PRS in non-Hispanic White and Black INHALE participants. Further validation of PRS could enable the incorporation of genetic risk modeling into lung cancer screening to identify patients who do not have traditional risk factors for lung cancer, as well as stratify patients into different levels of risk based on their genetic profile. Through the development of a reliable genetic risk factor prediction model, clinicians will have another method by which to evaluate lung cancer susceptibility, potentially leading to earlier diagnoses that portend more favorable treatment outcomes.