bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Budget impact model of LungFlag, a predictive risk model for lung cancer screening.
Authors: Gould Michael K. , Choman Eran Netanel , Olghi Nicolò , Obradovic Milan , Ogale Sarika , Heuser Sanmartin Carolina
Published: June 2024

10534

Background: Lung cancer screening (LCS) programs using low-dose computed tomography (LDCT) for early detection reduce mortality and have been widely recommended. LungFlag is a machine-learning risk prediction model that uses patient-level data to identify individuals at high risk of developing non-small cell lung cancer (NSCLC), prompting their physician to recommend screening with LDCT. Methods: A budget impact model was developed to estimate the costs associated with adoption of LungFlag as an adjunct to existing US Preventive Services Task Force (USPSTF) screening guidelines for a hypothetical US commercial health plan population of 1 million beneficiaries. The model calculates the total expected annual costs of screening for NSCLC with LDCT in scenarios with and without LungFlag, including healthcare resource utilization for detecting NSCLC and treatment of patients diagnosed with NSCLC. Incremental costs were evaluated over a 5-year period. Results: Among 36,803 USPSTF-eligible persons, we assumed that 4600 (12.5%) had already initiated LCS, leaving 32,203 persons who were candidates for pre-screening with LungFlag. The model estimated that 17 additional NSCLC diagnoses per year would be detected by screening when using LungFlag, with most in stage 1. Over 5 years, LungFlag was estimated to result in 33 fewer patients with stage 3 or stage 4 NSCLC at diagnosis and 22 fewer NSCLC-related deaths. Use of LungFlag increased annual costs during the first 2 years and provided cost savings from Year 4 onwards (Table). Cost savings from LungFlag were attributable to reductions in the costs of advanced NSCLC treatment. Conclusions: In a population of 1 million commercial health plan beneficiaries, the adoption of LungFlag as an adjunct to existing screening guidelines for USPSTF-eligible patients was estimated to prevent 22 additional NSCLC-related deaths, with a cost savings of $2.87 million over 5 years from a US commercial payer perspective. [Table: see text]
An emulated target trial assessing the impact of physical activity on 14-year cancer risk: Insights from the Cancer Prevention Study-II.
Authors: Elahy Valeria , McCullough Marjorie , Patel Alpa , Rees-Punia Erika , Peoples Anita R , Wang Ying
Published: June 2024

10541

Background: The American Cancer Society, along with the World Cancer Research Fund/American Institute of Cancer Research, recommends a weekly regimen of physical activity (at least 75 minutes of vigorous or 150 minutes of moderate-intensity aerobic physical activity) for cancer prevention. The positive impact of physical activity on reducing cancer risk is well-known; however, the causal link between physical activity and cancer risk reduction is not established, primarily due to the observational nature of the current evidence. Given the ethical considerations involved in assigning physical activity levels below the recommended minimum, coupled with the impracticality of conducting decades-long trials due to the latency period of cancer development, there is a need for an innovative approach beyond traditional observational and randomized trial methodologies. This highlights the importance of applying alternative strategies like emulated target trials to produce evidence of the causal effect of physical activity on cancer risk that would otherwise be difficult to obtain. This study aims to estimate the causal effect of adherence to recommended physical activity levels on the 14-year total cancer and obesity-related cancer risk using an emulated target trial framework. Methods: Data from 79,668 participants who were non-current smokers and without prevalent cancer diagnosis at pre-baseline in the Cancer Prevention Study-II were analyzed. This study estimated the effect of different physical activity levels (<7.5, 7.5-<15, and ≥15 MET-hrs/wk) on 14-year cancer risks using a parametric g-formula. Models adjusted for confounders include age, sex, education, years since quitting smoking, family history of cancer, physical activity, body mass index, alcohol consumption, diet quality (measured by the ACS diet score), history of cardiovascular disease, and diabetes. Results: Under no intervention, the estimated 14-year risk for any cancer was 27.9% (95% CI: 27.6%, 28.4%), and for obesity-related cancers, it was 11.2% (95% CI: 11.0%, 11.5%). Compared with no intervention, engaging in 7.5-<15 MET-hrs/wk of physical activity (minimum recommended) was linked with a 0.31% reduction in the risk of any cancer (95% CI: -0.41%, -0.06%) and a 0.19% reduction in the risk of obesity-related cancers (95% CI: -0.37%, -0.04%). Engaging in ≥15 MET-hrs/wk of physical activity (twice the minimum recommended level) was linked with a 1.31% risk reduction for any cancer (95% CI: -1.67%, -1.20%) and a 0.91% risk reduction for obesity-related cancers (95% CI: -1.09%, -0.80%), compared with no intervention. Conclusions: Incremental adherence to physical activity recommendations for cancer prevention could significantly lower the risk of developing cancers, including those related to obesity.
T cell-mediated rejection and cancer risk in 579,905 organ transplant recipients.
Authors: Kim Hye Sung , Woo Wongi , Shin Hyun Joon , Choi Young-Geun , Bharat Ankit , Chae Young Kwang
Published: June 2024

10552

Background: Prolonged immunosuppression following organ transplant raises post-transplant malignancy (PTM) risk without affecting chronic rejection graft failure (CRGF) rates. Our study investigated if T cell responses during rejection could protect against cancer, whereas T cell suppression in PTM might prevent rejection. Methods: Data from 1987 to 2023 on adult first-time single-organ transplant recipients were collected from the UNOS-OPTN database, excluding those with a history of malignancy. Time-dependent Cox regression and landmark analyses (at 1, 2, 3, 5, 10, 15, and 20 years) were used to explore the link between rejection-induced graft failure (RGF) and PTM. Results: The study included 579,905 recipients (kidney 386,878, liver 108,390, heart 45,046, lung 37,643, pancreas 1,948), with a mean follow-up of 7.3 years. RGF occurred in 9.5% of recipients (kidney 12.1%, liver 1.8%, heart 3.9%, lung 12.0%, pancreas 10.2%; p<0.001), with 2.1% experiencing acute rejection graft failure (ARGF) and 7.4%, CRGF. PTM occurred in 12.0% of recipients (kidney 9.9%, liver 12.4%. heart 20.9%, lung 22.6%, pancreas 11.3%; p<0.001), including breast (0.5%), digestive (1.2%), genitourinary (1.7%), gynecologic (0.1%), head and neck (0.3%), hematologic (1.4%), musculoskeletal (0.1%), neurologic (0.0%), respiratory (1.1%), and skin/Kaposi sarcoma (6.4%). In recipients with RGF, PTM risk significantly decreased (HR 0.21 [0.19-0.24]; p<0.001), with consistent trends observed across seven time landmarks (HR 0.20-0.07; p<0.001). Both ARGF and CRGF were associated with lower PTM risk (HR 0.23 [0.18-0.29], 0.21 [0.19-0.24]; p<0.001). In organ-specific analyses, kidney transplants showed similar outcomes for RGF, ARGF, and CRGF (HR 0.21-0.22; p<0.001). Lung transplants exhibited significant risk reductions with RGF (HR 0.44 [0.22-0.89]; p=0.02) and CRGF (HR 0.47 [0.24-0.94]; p=0.03), with no significant results in other organs. All findings remained consistent even after excluding re-transplantations and deaths due to rejection. Excluding PTM-related deaths from PTM cases significantly lowered RGF risk (HR 0.69 [0.65-0.73]; p<0.001), a trend that was consistent across all time landmarks (HR 0.51-0.80; p<0.001). This inverse pattern was seen in kidney, liver, heart, and lung transplants (HR 0.90 [0.84-0.95], 0.21 [0.11-0.38], 0.21 [0.14-0.31], 0.18 [0.14-0.23]; p<0.001) but not in pancreas transplants (HR 1.62 [0.69-3.77]; p=0.27). Conclusions: This study shows that rejection lowers cancer risk in kidney and lung transplants and that PTM reduces rejection risk in kidney, liver, heart, and lung transplants. Implementing enhanced cancer screening for those who have not experienced rejection may be considered. Further research is needed to elucidate the underlying T cell biology specific to each type of transplant.
Associations between violence, distress, and cancer in transgender and non-transgender people.
Authors: Alpert Ash Blythe , Sayegh Sabrina Jamileh , Cunliffe Scott , Sevelius Jae , Operario Don , Pachankis John , Irwin Melinda , Cerulli Catherine , Griggs Jennifer J. , Strawderman Myla S.
Published: June 2024

10566

Background: Due to transphobia, transgender people experience extreme rates of violence and distress. In other populations, violence and distress have been linked to increased cancer morbidity and mortality likely due to increased inflammation and higher rates of cancer risk factors. Methods: To evaluate associations between gender identity, violence, distress, cancer risk factors, and cancer, we developed an a priori structural equations model (SEM) and conducted a cross-sectional cohort study using electronic medical record data entered between 2006-2021 at a New York academic hospital. Participants were adults identified as transgender (N=894) by diagnosis codes, keyword searches, and structured gender identity information. We used age and follow-up time to match this cohort with participants not identified as transgender (N=1788) (2:1). We noted experiences of violence using keyword searches, diagnosis codes, and a screening question, “Are you safe at home?” We assessed distress as a latent factor based on mental illness diagnosis codes and keyword searches and diagnosis codes related to childhood violence. Cancer risk factors included ever smoking, body mass index ≥ 30, and history of HIV, HPV, or hepatitis B or C. We made unadjusted comparisons of violence, distress, cancer risk factors, and cancer in transgender and non-transgender people using two-sample chi-square tests. Our SEM included a direct path from gender identity to cancer or precancerous lesions as well as indirect paths through intermediaries of adult violence, distress, and cancer risk factors. We assessed direct paths for statistical significance using z-tests and indirect paths using bias-corrected bootstrap confidence intervals. Results: The association between gender identity and probability of cancer transmitted through the intermediate variables of violence, distress, and having multiple cancer risk factors was significant (p=0.05). Conclusions: In our model, transgender people experienced high rates of violence and distress, both of which were associated with cancer risk factors and cancer. Transphobia and violence experienced by transgender people must be addressed and mitigated. More work is needed to better understand associations between violence, distress, and cancer risk. [Table: see text]
Association between congenital heart disease and cancer: A meta-analysis of 30 million patients.
Authors: Batra Nitya , Jaiswal Vikash , Khosla Atulya Aman , Deb Novonil , Vadhera Ananya , Hanif Muhammad , Sawhney Aanchal , Hameed Maha , Jaiswal Akash , Ezekwudo Daniel , Jaiyesimi Ishmael A.
Published: June 2024

10568

Background: Birth defects have been associated with increased cancer risk; however, the association between congenital heart disease (CHD) and cancer risk has not been well established with limited and conflicting literature till date. Children afflicted with CHD possess multiple risk factors for oncogenesis, such as chromosomal and genetic abnormalities, ionising radiation exposure during cardiac imaging and interventions, chronic hypoxia and debility. We sought to evaluate the relationship between CHD and cancer risk and its various subtypes. Methods: We performed a systematic literature search on PubMed, EMBASE, and Scopus for relevant articles from inception until February 4th, 2023. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effects model, and a p-value of <0.05 was considered statistically significant. Results: A total of 5 studies with 30,437,431 patients (CHD group=213,229, and non-CHD group = 30,224,202) were involved in the analysis. Mean age of patients with CHD and non CHD was 48.4 and 51.3 years. The pooled analysis revealed that patients with CHD had a higher risk of skin cancer (OR, 1.16(95%CI: 1.10-1.24), p<0.00001), and thyroid cancer (OR, 1.47(95%CI: 1.20-1.80), p<0.001) compared with non-CHD patients. However, leukemia (OR, 0.74(95%CI: 0.22-2.48), p=0.62), gastrointestinal cancer (OR, 1.50(95%CI: 0.79-2.87), p=0.22), central nervous systems tumor (OR, 1.18(95%CI: 0.74-1.88), p=0.48), respiratory system cancer (OR, 0.94(95%CI: 0.67-1.30), p=0.69), breast cancer (OR, 95%CI: 0.96-1.48), p=0.87, genitourinary system cancer (OR, 1.06(95%CI: 0.73-1.54), p=0.76), and musculoskeletal cancer (OR, 1.40(95%CI: 0.92-2.41), p=0.12) was comparable between CHD and non-CHD groups of patients. Conclusions: Our findings indicate that CHD patients are at higher risk of thyroid and skin cancer compared with non-CHD patients; however, no such association with other cancers was observed. The implications of these results extend to the delineation of subsequent research, and the results underscore the necessity for further exploration into the underlying pathophysiological mechanisms. Potential implications include the establishment of enhanced surveillance and screening protocols to protect this vulnerable patient group. [Table: see text]
Metabolomics signatures of air pollution mixtures and lung cancer risk: A large-scale metabolome-wide association study in the Cancer Prevention Study cohorts.
Authors: Chow Sabrina S , Wang Ying , Sarnat Jeremy A , Diver Ryan , Deubler Emily L , Eick Stephanie M , Walker Douglas I , Tang Ziyin , Kesarwala Aparna H. , Turner Michelle , Liang Donghai
Published: June 2024

10571

Background: Despite the well-established link between air pollution exposure and lung carcinogenesis, the underlying mechanism remains underexplored. While metabolomics has provided valuable molecular insights, existing air pollution metabolomics studies only assess biological changes to single air pollutants, without examining the join effects of air pollutant mixtures. We sought to identify metabolic signatures mediating the association between ambient air pollution mixtures and lung cancer risk. Methods: A total of 603 matched lung cancer case-control pairs were selected from the Cancer Prevention Study cohorts. Controls were matched to cases on age at blood draw, sex, race/ethnicity, and blood draw date. Plasma metabolomics was conducted using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Air pollution mixtures include carbon monoxide, nitrogen dioxide, particulate matter, sulfur dioxide, and ozone, matched to subjects’ residential address at blood draw. We conducted an untargeted metabolome-wide association study with multivariable-adjusted linear and conditional logistic regression models to assess associations between metabolites and individual air pollutants and lung cancer risk, respectively, adjusting for individual and lifestyle-related covariates. We used a meet-in-the-middle (MITM) approach to identify potential mediators. Quantile g-computation was used to examine the effects of air pollution mixtures on metabolome perturbations to analyze the collective effects of multiple air pollutants concurrently. Results: Among 1,138 extracted metabolic features, 162 were significantly associated with the combined mixture (false discovery rate < 0.2). Using MITM, no metabolites were associated with both air pollution mixture and lung cancer risk at FDR < 0.2. At raw p < 0.05, 16 metabolites were identified as potential mediators of the air pollution mixture and lung cancer risk. These metabolites, including 4-hydroxyphenylacetylglutamine, glutamate, and 3-aminoisobutyrate, were also significantly associated with the mixture at FDR < 0.2. Conclusions: Findings from this analysis demonstrate the feasibility of considering multiple air pollutants as mixtures when conducting air pollution-related metabolomics investigations. Future exploration of the underlying biological mechanisms will be critical for validating pathways that participate in air pollution carcinogenicity. As lung cancer cases in never smokers continue to increase, it is pertinent to study air pollution and other environmental risk factors on cancer incidence.
Joint effects of long-term exposure to multiple air pollutants and breast cancer risk.
Authors: Fervers Béatrice , Giampiccolo Camille , Coudon Thomas , Praud Delphine , Grassot Lény , Faure Elodie , Severi Gianluca , Mancini Francesca Romana , Amadou Amina , Roy Pascal
Published: June 2024

10572

Background: Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effect of exposure to multiple air pollutants on breast cancer risk. We assessed the joint effects of multiple air pollutants and breast cancer risk. Methods: The study was based on a case-control study nested within the French E3N cohort, involving 5222 incident breast cancer cases and 5222 matched controls. For each woman, the average of the mean annual concentration estimates for eight air pollutants ((benzo(a)pyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO2), particulate matters (PM2.5, PM10), ozone) was estimated from cohort inclusion (in 1990) to the index date. We used Bayesian Profile Regression, which groups individuals according to their exposure profile and risk levels, and assigns a risk to each of these clusters. Odds ratios (OR) and their 95% credible intervals (CrI) were estimated. Results: Overall, 21 clusters were identified. The cluster characterized by low exposures to all pollutants, except ozone was taken as reference. A significant increase in breast cancer risk compared to the reference cluster was observed for 3 clusters, with the OR of 1.61 (CrI: 1.13;2.26), OR (1.00; 1.88), and OR 1.38 (1.00; 1.88) respectively. These three clusters share quite similar exposure profiles characterized by women in urban settings with high exposure to most pollutants, particularly to NO2, PM and PCB153. Conclusions: Overall, there is evidence of a positive joint effect of high level exposures to air several pollutants, namely NO2, PM and PCB153 and increased risk of breast cancer.
Uptake of risk-reduction, surveillance, and therapeutic interventions among patients with breast cancer with pathogenic germline variants.
Authors: Kurian Allison W. , Nielsen Young Sarah M. , Russell Emily M. , Facio Flavia , Moretz Chad , Heald Brandie , Ellsworth Rachel , Pineda-Alvarez Daniel , Esplin Ed , Korn W. Michael , Tung Nadine M.
Published: June 2024

10579

Background: Management of breast cancer (BC) patients with pathogenic germline variants (PGVs) can include risk-reducing bilateral mastectomy (BLM), PARP inhibitors (PARPi), enhanced breast imaging (MRI/tomosynthesis), risk-reducing salpingo-oophorectomy (RRSO) and pancreatic cancer surveillance (endoscopic ultrasound, EUS/MR cholangiopancreatography, MRCP). We assessed intervention uptake in >1,400 PGV-positive BC patients. Methods: Germline genetic testing (GGT) data (Invitae Corp.) and insurance claims data (Komodo Healthcare Map) were assembled for female patients with BC or DCIS diagnosed 2015-23, GGT <120 days from diagnosis, and >1 year of claims post-GGT. Inclusion/exclusion criteria followed prior work (PMID 32027353). Genes analyzed were those conferring high (>50%; BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53) or moderate (20-50%; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D) BC risk. Multivariable logistic regression models of intervention use included PGV risk, race/ethnicity, age, family cancer history, local metastasis, type of insurance, geographic region and time from diagnosis to GGT. Chi-square tests were used to compare intervention uptake rates by PGV risk (Table). Results: 1,432 patients had >1 PGV in a high- (51%) or moderate-risk (49%) gene: 68% White, 32% lymph node involvement, 69% BC family history, 28% Medicare/Medicaid, mean (SD) age at testing: 51 (12) and mean (SD) days from diagnosis to GGT: 40 (26). The intervention with the highest uptake was BLM (60% in all PGV carriers). BLM, RRSO, and PARPi were significantly more frequent in high- vs. moderate-risk PGV carriers. In the multivariable model, patients with BLM uptake were younger (odds ratio, OR 0.9, 95% confidence interval, CI 0.9-1), more often had family cancer history reported (OR 2, 95% CI 1-3) and had high-risk PGV (OR 5, 95% CI 3-7). Patients with RRSO uptake had higher odds of pancreatic (OR 2, 95% CI 1-2) or ovarian (OR 2, 95% CI 1-3) cancer family history and high-risk PGV (OR 6, 95% CI 4-8) and lower odds of Medicare (OR 0.4, 95% CI 0.2-0.8). Conclusions: Overall, the uptake of interventions was higher in patients with high- compared to moderate-risk PGV. More research, however, is needed on the shared decision-making process, as uptake of BLM was relatively high in those with moderate-risk PGV, and uptake of surveillance measures was relatively low.[Table: see text]
Evaluating genetic features and clinical characteristics of young women diagnosed with breast cancer by the age of 35.
Authors: Kurian Christine Jane , Abou Hussein Ahmed K. , Mattie Kristin , Hunter Krystal , Grana Generosa
Published: June 2024

10580

Background: Breast cancer in young women tends to be more aggressive with a unique distribution of molecular phenotypes compared to the general population. We evaluated the clinical characteristics and germline genetic test results in this cohort. Methods: We performed a single center retrospective review of 167 women diagnosed with breast cancer by 35, treated at our institution between the years 2013 to 2023. We reviewed medical records under Institutional Review Board approval for demographics, family history, tumor characteristics, surgical interventions performed, germline genetic test results, and number of pathogenic mutations identified. We used both descriptive and comparative quantitative statistics (student’s t test, Mann Whitney U Test and Chi Square tests) to compare data between patients with a pathogenic mutation and those without a pathogenic mutation. Results: Germline genetic testing was performed in 92.2% of individuals. The majority (81.4%) had no pathogenic mutation, whereas 15.6% had a pathogenic mutation implicated in hereditary breast cancer, and 3.0% had a pathogenic mutation not implicated in hereditary breast cancer. Our population was diverse - 60.4% white, 25.1% black, 7.8% Hispanic, and 6.5% Asian. Most patients had tumors that were high grade (56.3%), had a bilateral mastectomy performed (57.4%), did not have recurrence (87.4%), had exposure to oral contraceptives prior to diagnosis (59.9%), and had a family history of breast cancer (52.1%). 3.5% of patients were pregnant at the time of diagnosis. 26 patients were found to have pathogenic mutations implicated in hereditary breast cancer including BRCA1 (10), BRCA2 (10), CHEK2 (2), TP53 (2) and 88.5% of these patients underwent bilateral mastectomy. A higher proportion of patients with a pathogenic mutation were found to be progesterone receptor (PR) negative (56.8% vs 34.9; p = 0.029), undergo bilateral mastectomy (80.8% vs 53.2%; p = 0.009), be stage 1 at diagnosis (50.0% vs 19.1%; p < 0.001), have invasive ductal carcinoma (80.8% vs 59.6%; p = 0.040), and have a family history of breast cancer (73.1% vs 48.9%; p = 0.024) compared to those with no pathogenic mutation. While not statistically significant, a higher proportion of patients with pathogenic mutations experienced recurrence (19.2% vs 11.3%; p = 0.330). Conclusions: Our study showed that breast cancer diagnosed in young women has a more aggressive disease biology with 56.3% of the cohort found to have grade 3 disease. A higher proportion of those who had a pathogenic mutation implicated in hereditary breast cancer were found to be PR negative, underwent bilateral mastectomy, and had a family history of breast cancer. As our study was an exploratory observational study, further prospective multi-center studies are needed to help corroborate our findings and to better elucidate the potential clinical significance.
Association of germline HSD3B1 (c.1100) genotype with tumoral and clinical outcomes in breast and endometrial cancers.
Authors: Hwang Justin , Nazari Shayan , Elliott Andrew , Vanderwalde Ari M. , Lange Carol A , Geller Melissa Ann , Ryan Charles J. , Nabhan Chadi , Sharifi Nima , Antonarakis Emmanuel S.
Published: June 2024

10587

Background: A germline single-nucleotide polymorphism in HSD3B1 results in adrenal-permissive (c.1100 C) and adrenal-restrictive (c.1100 A) phenotypes with respect to androgen synthesis. In pre- and post-menopausal patients with breast cancer (n=3548 and 7871) and endometrial cancer (n=1588 and 8439), we annotated samples as adrenal permissive (CC/AC) or restrictive (AA) based on HSD3B1 variant status and then examined tumoral characteristics and clinical outcomes. Methods: We utilized tumors from the Caris Life Sciences Precision Oncology Alliance database and inferred germline HSD3B1 c.1100 genotype using variant allele frequencies (VAFs): c.1100 C VAF of 0% defined the AA genotype, VAF of 40-60% defined the AC genotype, and VAF of 100% defined the CC genotype. We explored associations of each HSD3B1genotypes with other genomic (WES) and transcriptomic (RNA-seq) features, as well as with survival outcomes. To performed consider menopausal status we used the patient’s age at the time of biopsy (>55 indicating post-menopausal). Results: In breast cancer (BC) and endometrial cancer (EC), the permissive HSD3B1genotype had greater mRNA expression of the estrogen receptor ( ESR1) and co-alterations of the TP53 (p<0.0001). In post-menopausal ECs, the permissive genotype was associated with increased alterations in the PI-3-kinase pathway ( PTEN, PIK3CA, PIK3R1, p<0.0001). In pre-menopausal HER2+ BCs, the restrictive genotype was associated with worse survival (HR=1.40, 95% CI = 1.05-1.85, p=0.027) and exhibited increases in hallmark GSEA signatures including epithelial-to-mesenchymal transition. Post-menopausal basal BCs with the permissive genotype had numerically higher PD-L1 protein expression (50% vs 13%) and less PI-3-kinase alterations ( PTEN, PIK3R1, p<0.01). Post-menopausal clear cell ECs with the restrictive genotype exhibited worse survival (HR=1.60, 95% CI=1.07-2.38, p=0.03) and were 3-fold more likely to be TMB-high or MSI-high (p<0.05). Distinctly, post-menopausal endometrioid ECs of the restrictive genotype were less likely to be TMB- or MSI-high (p<0.05). Conclusions: Breast and endometrial cancers can be classified as adrenal-permissive or -restrictive based on HSD3B1 c.1100 genotype. This classification distinguishes clinical outcomes and tumoral features, particularly when stratifying by menopausal status. Importantly, these genotypes are differentially associated with druggable pathways (PI-3-kinase) and markers of immune sensitivity (PD-L1, TMB, MSI). [Table: see text]