Anne Krogh Nøhr

Background: Polygenic risk scores (PRS) show potential for risk-based colorectal cancer (CRC) screening, but their utility must be assessed across diverse ancestries and tumour characteristics and compared with the current standard, the faecal immunochemical test (FIT). Design: The cohort included 112,204 individuals from the Copenhagen Hospital Biobank (8995 with adenoma and 9246 with CRC), all with linked genetic and health registry data. A subset ( N = 20,658) also had FIT results. CRC PRSs were evaluated for their association with lifetime adenoma and CRC risk and their predictive value individually and combined with FIT. Results: PRS stratified population-calibrated lifetime adenoma and CRC risk independently of ancestry and sex. Individuals with a high PRS reached the incidence of low-PRS individuals up to 10 years earlier, between ages 45–60. PRS stratified risk across tumour location and histologies but showed no association among individuals with deficient mismatch repair tumours ( N = 623). Combining PRS with FIT did not meaningfully improve prediction of adenoma or CRC at first screening, negative colonoscopy outcomes among FIT-positive participants, or outcomes within 2 years after a negative FIT. Conclusion: PRS stratifies lifetime adenoma and CRC risk and may inform risk-based screening initiation and intensity but adds limited predictive value when combined with FIT.

Background: Aggregating effects of common genetic variants into a polygenic risk score (PRS) has shown potential for risk-based colorectal cancer (CRC) screening. However, its utility must be evaluated in ancestrally diverse populations with diverse tumor characteristics and compared to the current screening standard, the fecal immunochemical test (FIT). Objective: Evaluate the utility of PRS for risk-based CRC screening. Design: The cohort included 112,204 individuals from the Copenhagen Hospital Biobank (8,995 with adenoma and 9,246 with CRC), all with linked genetic and health registry data. A subset (N=20,658) also had available FIT results. CRC PRSs were evaluated for their association with lifetime adenoma and CRC risk and their predictive value individually and combined with FIT. Results: PRS stratified population-calibrated lifetime adenoma and CRC risk independently of ancestry and sex. Incidence curves showed that individuals with a high PRS reached the incidence levels of low-PRS individuals around 10 years earlier, between ages 45 to 60. PRS also stratified risk across tumor location and histology but showed no association among individuals with deficient mismatch repair tumors (N=623). Predictive modeling indicated that combing PRS with FIT did not meaningfully improve prediction of adenoma or CRC at first screening, negative colonoscopy outcomes among FIT-positive participants, or adenoma or CRC occurrence within two years after a negative FIT. Conclusion: PRS effectively stratifies lifetime adenoma and CRC risk and shows promise for guiding risk-based screening initiation and intensity. When combined with FIT, it adds limited additional predictive value.

Numerous clinical trials have attempted to improve first-line R-CHOP treatment of diffuse large B-cell lymphoma (DLBCL) through the addition or substitution of drugs. The REMoDL-B trial, testing the addition of bortezomib (RB-CHOP), revealed that ABC and molecular high-grade DLBCL patients benefit from bortezomib. The aim of this study was to achieve a better understanding of the bortezomib response in DLBCL through a functional investigation of clinically identified markers. A retrospective analysis of transcriptional and clinical data from the REMoDL-B trial was conducted to identify genes associated with bortezomib response, identifying CDCA2. DLBCL patients with high expression of CDCA2 had a superior survival outcome when treated with RB-CHOP in comparison to R-CHOP, whereas no difference in outcome was observed for patients with low CDCA2. Moreover, CDCA2 was found to be overexpressed in DLBCL compared to non-malignant tissue, and to have higher levels in GCB and MYC/BCL2 double-expressor patients. Functional in vitro and in vivo studies revealed that knockout of CDCA2 decreased DLBCL cell proliferation and a bortezomib dose–response analysis showed less sensitivity in CDCA2 knockout cells compared to control cells. This study shows that DLBCL patients with high CDCA2 expression benefitted from the addition of bortezomib to R-CHOP and functional studies documented a direct impact of CDCA2 on the bortezomib response in DLBCL cells.

Background: Not all patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs). Therefore, we aimed to assess the predictive potential of gene expression profiling (GEP), peripheral immune cell counts, and clinical characteristics. Methods: The primary endpoint of this prospective, observational study was a durable clinical benefit (DCB) defined as progression-free survival >6 months. In a subgroup with histological biopsies of sufficient quality (n = 25), GEP was performed using the nCounter^® PanCancer IO 360 panel. Results: DCB was observed in 49% of 123 included patients. High absolute lymphocyte count (ALC) and absence of liver metastases were associated with DCB (OR = 1.95, p = 0.038 and OR = 0.36, p = 0.046, respectively). GEP showed clustering of differentially expressed genes according to DCB, and a strong association between PD-L1 assessed by GEP (CD274) and immunohistochemistry (IHC) was observed (p = 0.00013). The TGF-β, dendritic cell, and myeloid signature scores were higher for patients without DCB, whereas the JAK/STAT loss signature scores were higher for patients with DCB (unadjusted p-values < 0.05). Conclusions: ALC above 1.01 × 10⁹/L and absence of liver metastases were significantly associated with DCB in ICI-treated patients with NSCLC. GEP was only feasible in 20% of the patients. GEP-derived signatures may be associated with clinical outcomes, and PD-L1 could be assessed by GEP rather than IHC.