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Background Polygenic risk scores (PRS) are not yet standard in clinical risk assessments for familial breast cancer in Sweden. This study evaluated the distribution and impact of an established PRS (PRS 313 ) in women undergoing clinical sequencing for hereditary breast cancer. Findings We integrated PRS 313 into a hereditary breast cancer gene panel used in clinical practice and calculated scores for 262 women. Comparisons were made between women with unilateral and contralateral breast cancer, as well as those with and without pathogenic variants in breast cancer susceptibility genes. PRS 313 was significantly higher in women with contralateral breast cancer (median + 1.3 SD, n  = 33, P  = 8e-9) compared to those with unilateral disease (median + 0.66 SD, n  = 197, P  = 5e-10). Elevated PRS 313 was also observed in women with pathogenic variants, including those in high-penetrance genes (+ 0.65 SD) and moderate-penetrance genes (+ 0.93 SD), compared to population controls. Incorporating PRS 313 into a clinical risk model (BOADICEA), shifted 20%-27% of women with moderate-penetrance variants and 23%-32% of women without pathogenic variants into different risk categories according to NCCN and NICE guidelines. Conclusions Women with familial breast cancer showed elevated PRS 313 , including those with pathogenic variants, contributing to the observed high risk in these families. Integrating PRS into risk assessment and genetic counselling has the potential to refine risk predictions, even among women with breast cancer attributed to monogenic variants.

Aberrant pro-survival signaling is a hallmark of cancer cells, but the response to chemotherapy is poorly understood. In this study, we investigate the initial signaling response to standard induction chemotherapy in a cohort of 32 acute myeloid leukemia (AML) patients, using 36-dimensional mass cytometry. Through supervised and unsupervised machine learning approaches, we find that reduction of extracellular-signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the myeloid cell compartment 24 h post-chemotherapy is a significant predictor of patient 5-year overall survival in this cohort. Validation by RNA sequencing shows induction of MAPK target gene expression in patients with high phospho-ERK1/2 24 h post-chemotherapy, while proteomics confirm an increase of the p38 prime target MAPK activated protein kinase 2 (MAPKAPK2). In this study, we demonstrate that mass cytometry can be a valuable tool for early response evaluation in AML and elucidate the potential of functional signaling analyses in precision oncology diagnostics. The molecular mechanisms underlying response to chemotherapy in Acute myeloid leukemia (AML) remain to be explored. Here, the authors perform 36-dimensional mass cytometry in 32 AML patients during intensive chemotherapy and suggest functional signalling analysis for prognosis prediction early after treatment in AML.

Intratumoral heterogeneity is an important clinical challenge because low burden clones expressing specific genetic alterations drive therapeutic resistance mechanisms. We have developed CAVE ( cancer-associated variant enrichment ), a gene-agnostic computational tool to identify specific enrichment of low-burden cancer driver variants in next-generation sequencing (NGS) data. For this study, CAVE was applied to TP53 in chronic lymphocytic leukemia (CLL) as a cancer model. Indeed, as TP53 mutations are part of treatment decision-making algorithms and low-burden variants are frequent, there is a need to distinguish true variants from background noise. Recommendations have been published for reliable calling of low-VAF variants of TP53 in CLL and the assessment of the background noise for each platform is essential for the quality of the testing. CAVE is able to detect specific enrichment of low-burden variants starting at variant allele frequencies (VAFs) as low as 0.3%. In silico TP53 dependent and independent analyses confirmed the true driver nature of all these variants. Orthogonal validation using either ddPCR or NGS analyses of follow-up samples confirmed variant identification. CAVE can be easily deployed in any cancer-related NGS workflow to detect the enrichment of low-burden variants of clinical interest.

Missense mutations that inactivate p53 are common in cancer. LiFraumeni syndrome, which is linked to early-onset cancer, is caused by germline mutations in TP53 . Full-penetrant, inactive variants have garnered great attention, whereas low-penetrant variants are less well understood despite their clinical importance. This study systematically leveraged the 2025 UMD_TP53 database to identify missense variants that exhibit a statistically skewed germline-versus-somatic ratio (GVSr). Unlike classic hotspots that are equally prevalent in somatic and germline settings, these variants were disproportionately found in the germline, suggesting they act as low-penetrance variants with insufficient potency to drive tumorigenesis as single somatic events. To define the biological basis of LPVs, we integrated functional data from multiplexed assays of variant effects, tumor cell transcriptome analyses and computational predictive tools. This characterization revealed that these high-GVSr p53 variants consistently retain intermediate transcriptional activity and growth-suppressive function, classifying them distinctively as hypomorphic alleles rather than loss-of-function mutants. Our findings highlight the complexity of TP53 variant effects and underscore the importance of refined functional classification. Recognizing and accurately characterizing hypomorphic variants associated with low-penetrance cancer risk are essential for precision oncology, as they will improve genetic counseling, risk stratification, and tailored surveillance strategies for individuals with TP53 mutations.

Increasing recognition of germline DDX41 variants in patients with hematological malignancies prompted us to provide DDX41‐specific recommendations for diagnosis, surveillance, and treatment. Causative germline variants in the DDX41 predispose to the development of myeloid neoplasms (MNs), especially myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Almost 3%–5% of all patients with MDS or AML carry a pathogenic or likely pathogenic germline DDX41 variant, while half of them acquire a somatic second hit in the other allele. DDX41‐associated MNs exhibit unique clinical characteristics compared to other hematological malignancies with germline predisposition: MNs occur mostly at advanced age and follow an indolent clinical course. Male carriers are more prone to develop MDS or AML than females. DDX41‐associated MN is often hypoplastic, and the malignancy may be preceded by cytopenias.

Background Genomic profiling of patients with myeloid neoplasms (MN) may detect variants with high variant allele frequency (VAF), indicating potential germline origin. All current guidelines recommend further investigation of such variants. Objective To define the proportion of variants with suspected germline origin that prompted germline investigation in patients evaluated for MN in the clinical setting. Methods We included 738 patients investigated for MN in Mid‐Sweden between May 2020 and January 2023 with available sequencing data in genes of interest (GOI) according to the Nordic and other international guidelines. Results In total, 90 patients (12%) carried pathogenic/likely pathogenic (P/LP) variants in GOI according to the Nordic guidelines, with TP53, RUNX1, and NRAS being the most common (n = 37, n = 27, and n = 9, respectively). The potential germline origin was investigated in 16/90 (18%) patients. Two patients (2/16, 12.5%) with germline variants were identified (DDX41 and RUNX1, n = 1, respectively). In patients treated with allogeneic stem‐cells transplantation (n = 15) the investigation rate was higher (7/15, 47%, p < 0.005) compared to the non‐transplanted ones. Applying the European Leukemia Net (ELN) guidelines the number of patients with variants in GOI increased up to 177 mainly due to the inclusion of TET2, while application of other international guidelines leads to similar results with the Nordic ones. Conclusion We report a low investigation rate for variants of suspected germline origin detected during the genomic profiling of patients investigated for MN in the clinical setting. Our study underscores the need for further awareness regarding germline investigation for hematological malignancies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.