Citations

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

ABSTRACT Background Prolonged QT interval is common in end‐stage renal disease (ESRD) on dialysis, but its long‐term cardiovascular (CV) implications remain unclear. Methods Using TriNetX network (2010–2024), we identified adults with ESRD on dialysis and categorized them by QTc status. After 1:1 propensity score matching ( n = 3428/group), outcomes (hazard ratio [HR]) were assessed using Cox regression. Results Prolonged QTc (> 500 ms) was associated with higher risk of all‐cause mortality (HR 1.67; p < 0.001), MACEs (HR 1.40; p < 0.001), cardiac arrest (HR 1.75; p < 0.001), sustained ventricular arrhythmia (HR 1.66; p < 0.001), new‐onset atrial fibrillation (HR 1.12; p = 0.01), and acute myocardial infarction (HR 2.19; p < 0.001). Conclusions In ESRD patients on dialysis, prolonged QT interval was independently associated with adverse CV outcomes and mortality.

Abstract Uptake of tamoxifen is limited to 5-15% of all eligible women due to concerns regarding medication side effects combined with the lack of ability to predict which women will benefit from the therapies. We used a unique retrospective sample of n=92 high-risk women with paired benign biopsies obtained before (PreTam) and during tamoxifen (OnTam) to discover tissue gene expression biomarkers of biologic response, defined as change (Δ) in lobular Ki67. Ki67 was digitally quantified in normal lobules from PreTam and OnTam benign tissue samples and samples with PreTam Ki67 = 0 were excluded. Data were analyzed from 51 women with both PreTam and OnTam Ki67 (median age = 49 years and median BMI = 25.5 kg/m2 at PreTam biopsy). OnTam biopsies were collected a median of 11.5 months after PreTam biopsy (median 6.5 months after starting tamoxifen; dose 20 mg/day in 86%). Median Ki67 significantly decreased overall (Δ Ki67 = -0.29%, p=0.003), but the effect was restricted to women with baseline Ki67 ≥ 0.5% (n=38, Δ Ki67 = -0.78%, p=0.0002); no significant change occurred with baseline Ki67 &lt; 0.5 (Δ Ki67 = 0.19%, p=0.23). Δ Ki67 was inversely proportional to baseline Ki67. RNA-seq was successful for 171 benign tissue samples (including 53 PreTam-OnTam pairs). After edgeR normalization (&gt;14,600 genes), PreTam vs OnTam comparison across 33 pairs with baseline Ki67 ≥ 0.5% yielded 66 differentially expressed genes (fold-change &gt; 2 and p&lt;0.01). At p&lt;0.01, ranked gene set enrichment analysis revealed 27 gene sets enriched for reduced expression with Tam (with top-ranked gene set related to steroid hormone biosynthesis) and 59 gene sets enriched for increased expression with Tam (with top-ranking gene sets related to B cell and T cell receptor signaling, regulation of cell cycle, and other immune-related pathways). To identify predictors of response, we correlated baseline PreTam gene expression with Δ Ki67 in 37 women with available baseline PreTam RNAseq and Δ Ki67 data. Partial correlation analysis (via ‘ppcor’ package, adjusted for library qubit) revealed 73 genes with significant positive correlation (rho &gt; 0.50) and 14 genes with significant negative correlation (rho &lt; -0.50) with Δ Ki67 (p&lt;0.01). At p&lt;0.01, ranked gene set enrichment analysis yielded 67 gene sets enriched with negative correlation (i.e. increased expression associated with a reduction in Ki67), including pathways related to ribosome biogenesis, DNA recombination, and nucleic acid metabolic processes; there were 62 gene sets enriched for positive correlation (i.e. decreased expression associated with a reduction in Ki67), including pathways such as VEGF and ERBB signaling. Our data support (i) baseline Ki67 ≥ 0.5 % and (ii) an 87-gene baseline signature as complementary biomarkers of tamoxifen response. Prospective validation of this combined assay could target tamoxifen to the women most likely to benefit, potentially overcoming a major barrier to chemoprevention uptake. Citation Format: S. J. Winham, C. Wang, Y. Liu, B. M. McCauley, D. J. Tabrizi, D. L. Gehling, J. L. Fischer, L. R. Seymour, M. H. Solanki, M. E. Sherman, K. R. Lohani, T. L. Hoskin, D. C. Radisky, A. C. Degnim. Gene expression signatures of beneficial response to tamoxifen for breast cancer prevention [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-18.

Abstract Background: Artificial intelligence (AI) algorithms based on deep learning approaches show promise in improving breast cancer (BC) detection on mammography and may also improve prediction of future BC risk compared with clinical risk prediction models. Historical clinical risk prediction models underperform among women with BBD; however, AI models for BC detection on mammography have not been tested among women at elevated BC risk due to benign breast disease (BBD). We evaluated if an AI cancer detection algorithm can aid BC risk prediction among women with BBD. Methods: We examined women without a prior BC who had an initial BBD biopsy at Mayo Clinic, Rochester, between 2002 and 2013. Incident BC occurring after BBD was identified using the Mayo Tumor Registry and supplemented by follow-up questionnaires. Only women with a full field digital mammogram at least 2 years prior to BC diagnosis were eligible. A breast pathologist evaluated BBD according to increasing severity, as non-proliferative (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH). AI malignancy scores derived from the Transpara detection algorithm (1-10) and volumetric percent density (VPD) from Volpara (per one standard deviation, SD) were assessed from mammograms close to BBD diagnosis. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) with 95% Confidence Intervals (CIs), adjusted for age and BMI. C-statistics were estimated to assess the contribution of each factor to BC risk prediction. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance with the addition of AI malignancy score. Results: The BBD cohort with mammography consisted of 3,125 women followed for a median 12.9 years, with 250 incident BC. Of these, 221 BC occurred at least two years after the mammogram and were used in analyses. As expected, increased BC risk was associated with BBD severity [for AH HR=3.18 (95%CI: 2.04, 4.95) and for PDWA HR=1.59 (95%CI: 1.17, 2.14) compared to NP] and with higher VPD [HR=1.24 per SD (95% CI: 1.05, 1.45)] (Table ). The AI-malignancy score alone was also associated with BC risk [HR=1.16 per 1 unit score (95%CI: 1.09,1.23)] and showed similar discriminatory accuracy [C-statistic=0.626 (95%CI: 0.586, 0.665)] as the model with BBD severity and VPD combined [C-statistic=0.627, (95%CI: 0.585, 0.669)] (Table ). In models with BBD severity and VPD, the AI-malignancy score was an independent risk factor for BC [HR=1.14 (95%CI: 1.07, 1.21); PLRT&lt;0.001] but only achieved a marginally significant improvement in discriminatory accuracy [C-statistic=0.651 (0.609, 0.693), ΔC-statistic=0.024 (95% CI: 0.000, 0.047)]. Conclusion: In this preliminary study, an AI BC detection algorithm achieved similar performance in predicting future BC risk compared to established risk factors. Citation Format: C. M. Vachon, S. Winham, M. Jensen, D. Hursh, L. Pacheco-Spann, A. Norman, J. Fischer, S. Schrup, L. Seymour, D. Gehling, S. Nyante, M. Troester, N. Karssemeijer, R. Vierkant, D. Radisky, C. Scott, S. I. Maimone, A. Degnim, M. Sherman. An AI algorithm for breast cancer detection improves future BC risk prediction among women with benign breast disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-02.

ABSTRACT Myhre syndrome is a rare multisystem disorder characterized by distinctive facial features, hearing loss, and progressive fibrosis affecting the skin, joints, lungs, and cardiovascular system. It is caused by heterozygous pathogenic variants in the SMAD4 gene. In this review, we detail the cutaneous manifestations observed in two previously reported patients with genetically confirmed Myhre syndrome. While skin biopsies demonstrated pan‐dermal thickening of collagen bundles, the immunohistochemical staining patterns were distinct from those seen in other inflammatory sclerosing disorders. Additionally, we conducted a comprehensive literature review of the cutaneous features associated with Myhre syndrome, identifying 175 patients with confirmed SMAD4 pathogenic variants. The most reported cutaneous finding was thickened or stiff skin (76%), followed by keratosis pilaris (22%) and impaired wound healing or abnormal scarring (18%). Genotype–phenotype analysis suggested a diagnostic delay in patients with the codon 496 variant, who were more frequently diagnosed in adulthood. This variant may also be associated with a milder cutaneous phenotype, highlighting the clinical heterogeneity of Myhre syndrome. These findings underscore the importance of recognizing cutaneous features as potential early diagnostic clues in patients with suspected Myhre syndrome.

Abstract Objective To test the effectiveness of a surgical web‐based decision aid (DA) in improving knowledge. Summary of Background Data DAs support decision making by providing information about the options. Methods A stepped wedge trial was conducted in 10 National Cancer Institute Community Oncology Research Program clinics (Alliance for Clinical Trials in Oncology). Clinics were randomized to time of transition from usual care (UC) to delivery of a web‐based DA. Patients with stage 0 through 3 breast cancer being considered for surgery were enrolled. Knowledge (primary outcome) was measured using the Breast Cancer Surgery Decision Quality Instrument and patients were asked, “How informed do you feel?” Intervention effects were tested with linear mixed‐effects models, accounting for surgeon and clinic‐level clustering, time, and enrollment after COVID. Additional models controlled for demographics. Results A total of 44% of DA arm patients reviewed the DA and 58% in UC arm reported reviewing “any information.” Being in the DA arm versus UC was not associated with knowledge. However, “review of information” was associated with higher knowledge. In addition, non‐White race and lower education were associated with lower knowledge. The DA arm was associated with higher perceptions of feeling informed (parameter estimate 1.36; 95% CI, 0.18–2.55; p = .02); this persisted even when controlling for review of information or demographics. Conclusion Improved knowledge was not demonstrate with a web‐based DA versus UC. Interestingly, the DA was associated with a higher likelihood of feeling informed. Future research will explore the discrepancy between patients feeling informed but having low knowledge, especially for disadvantaged patients. Trial Registration ClinicalTrials.gov Identifier: NCT0376600

Abstract Sinonasal squamous cell carcinoma (SNSCC) is an aggressive head and neck cancer of the sinonasal cavity which has not benefitted from therapeutic advances over decades 1 . Though historically attributed to inhaled carcinogens such as hardwood dust and tobacco smoking 2 , SNSCC is incidentally associated with human papillomavirus (HPV) 3,4 . Importantly, HPV is the primary oncogenic driver of >80% of anatomically adjacent oropharyngeal cancers 5 . While viral status drives clinical staging and treatment guidelines in these malignancies 6,7 , the potentially oncogenic consequences and prognostic value of host–virus interactions in SNSCC remain incompletely defined. Here, through paired host and viral whole-genome sequencing (WGS), we map the genomic footprint of HPV in SNSCC. Strikingly, lesser studied strains such as HPV45, 51, and 39 constitute driver infections in this rare but clinically credentialed cancer, where extrachromosomal DNA (ecDNA)-associated viral integration and APOBEC mutagenesis are shown to underpin somatic tumor evolution. Statement of Significance Paired host viral and whole-genome sequencing of SNSCC nominates HPV as a primary oncogenic driver of SNSCC. HPV–human ecDNA amplicons harboring noncanonical strains such as HPV45, 51 mediate viral carcinogenesis. Routine clinical diagnostic HPV panels should be expanded to capture the activity of lesser studied strains.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vaginal Cancer outline the recommended diagnostic workup, staging considerations, and treatment options for this rare malignancy. Because vaginal cancer is uncommon and shares many biologic and clinical characteristics with cervical cancer, several management recommendations, particularly systemic therapy, are extrapolated from evidence and practices established for cervical cancer. This guideline excerpt summarizes key components of management, including diagnostic evaluation and workup, principles of staging, pathology considerations, radiation therapy principles, and primary treatment recommendations for both early-stage and advanced disease. It also details approaches to manage relapses, including locoregional recurrence and distant metastases, and provides an in-depth overview of systemic therapy recommendations for vaginal cancer.

Abstract Background Women with advanced chronic kidney disease (CKD) encounter reproductive health challenges, including reduced fertility, menstrual irregularity, and sexual dysfunction. This study examined changes in sex hormones in patients with CKD, their correlation with sexual function, and changes after transplant. Methods This study recruited women aged 18–51 years with CKD stages 3b-5 from outpatient clinics and dialysis units. Exclusion criteria included active pregnancy, menopause, prior hysterectomy/bilateral oophorectomy, or use of hormonal contraceptives/therapy. Data were collected at enrollment and at 6 months post-transplant. Results Thirty-eight subjects met eligibility criteria and enrolled in the trial (8 in CKD stage 3b, 10 in CKD stage 4, and 20 in CKD stage 5/5D). Sexual dysfunction (25/38, 65.8%), defined as total female sexual function index score &lt; 26.55, and menstrual irregularities (17/38, 44.7%) were common, with abnormal elevation of luteinizing hormone present in the follicular phase in the majority of patients. There was a significant negative association between total female sexual function index score and prolactin (β = -0.26, P = 0.03) and dehydroepiandrosterone sulfate (β = -0.07, P = 0.01) after adjusting for age. After transplant, there was also a significant improvement in both prolactin and dehydroepiandrosterone sulfate levels, although sexual dysfunction persisted. Conclusions This study highlights the complex interplay between advanced CKD, reproductive endocrinology, and sexual health. Significant hormonal dysregulation and associated reproductive challenges were observed. The prominent role of dehydroepiandrosterone sulfate in sexual dysfunction among women with CKD requires further study.

Background and aims: Aberrations in telomere length can have important implications in cancer. Using a cohort of 1007 patients, we investigated whether leukocyte telomere length (LTL) in patients with colorectal cancer (CRC) is associated with survival. We also investigated whether some telomere maintenance genes are associated with survival in these patients. Methods: The Biobank for Gastrointestinal Health Research (BGHR), an ongoing project involving collection of biospecimens at the Mayo Clinic, was utilized to obtain data from patients diagnosed with stage II or III CRC. Blood samples were collected prior to chemotherapy/radiation and DNA was extracted for measuring median LTL. The main outcome measures were overall survival (OS) and disease-free survival (DFS) by disease stage. Results: A significant inverse relationship was observed with patient age and LTL (spearman correlation coefficient (r) = −0.48, 95%; p = 1.13 × 10−58). Females had significantly longer LTL than males (p = 3.97 × 10−5). The rs1317082 SNP in the TERC gene was significantly associated with both OS and DFS in combined stage II and stage III patients (p = 0.017 and p = 0.023, respectively). A statistically significant association of the OBFC1 SNP (rs9419958) was observed for OS for the combined stage II and stage III patients (p = 0.016). Importantly, LTL was significantly associated with both OS and DFS (p = 0.008 and 0.044 respectively) in combined stage II and stage III patients. Conclusions: Our results show that LTL is predictive of OS and DFS for stage II and III CRC patients, particularly over a longer follow-up, extending beyond five years after a diagnosis of CRC, and certain SNPs in genes involved in telomere maintenance are significantly associated with patient outcomes, independent of telomere length.