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PubMed2025

Concerns about the consequences of cancer predisposition and relationships with quality of life in young adults with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; Mage = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental (M = 65.8), physical (M = 67.5), and general (M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores (M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = -0.491, 95% CI -0.76, -0.22, p < 0.001) and general HRQOL (β = -0.466, 95% CI -0.77, -0.16, p = 0.004), but not mental HRQOL (p = 0.102). CC-LFS accounted for significant proportions of unique variance in general (R2adj = 17.7%, p = 0.004) and physical HRQOL (R2adj = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs' psychosocial health.

Humans↗

PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗

PubMed2026

Human-AI Interaction With AI-Assisted Tumor Overlays in Pediatric Whole-Body Magnetic Resonance Imaging: Exploratory Reader Study.

BACKGROUND: AI tools have the potential to enhance personalized clinical care, particularly in radiology. However, their integration into clinical workflows remains complex, especially in pediatric oncology, where early cancer detection is critical. Children with Li-Fraumeni syndrome (LFS), a rare cancer predisposition disorder, undergo regular surveillance whole-body magnetic resonance imaging (wbMRI), which presents an opportunity for AI-assisted tumor detection. OBJECTIVE: We evaluated the feasibility of an AI-assisted overlay for highlighting tumor-like regions in pediatric surveillance wbMRI and explored how access to the overlay influenced radiologist workflow, candidate-lesion marking behavior, follow-up recommendations, and perceived workload. METHODS: We developed a patch-based AI segmentation model trained on augmented 2D slices from 675 surveillance wbMRI volumes of pediatric patients with LFS. The model was designed to highlight regions with high tumor probability. A reader study was conducted with 2 radiologists who independently reviewed wbMRI cases both with and without AI assistance. We measured evaluation time, number and location of reader-marked candidate lesions, type of follow-up recommendation, and subjective feedback using structured questionnaires. RESULTS: AI assistance altered interpretation workflows for both radiologists, with mixed effects. On average, the time required to evaluate each case increased when using the AI tool for both radiologists. However, one radiologist had an increase in the number of candidate lesion locations selected with the tool, and one had a decrease in the number of candidate lesion locations selected with the tool. Subjective feedback indicated that one of the radiologists reported lower mental demand with the AI tool, while both radiologists reported lower stress with the AI tool. Interrater variability was evident, underscoring the need for personalized calibration of AI tools. CONCLUSIONS: AI-assisted wbMRI interpretation can improve tumor detection in pediatric cancer surveillance by reducing false negatives. However, its influence on workflow efficiency and interradiologist variability highlights the importance of careful implementation. Successful integration requires addressing challenges such as improving the predictive precision of AI models, offering intuitive end-user designs and instructions, and building trust in AI outputs. AI outputs can influence workflow and behavior in reader-specific ways. Clinical translation will require larger, randomized, multireader studies and model refinement to reduce false positives and quantify lesion-level reader performance. This can help ensure better patient outcomes in addition to reduced clinician burnout.

Humans↗

PubMed2024

[Pathogenic large duplication in TP53 as a hereditary predisposing factor in breast cancer].

AIM: Germline pathogenic variants of TP53 are associated with Li-Fraumeni syndrome and represent a high risk for hereditary breast and ovarian cancer. We identified a germline, multi-exon heterozygous duplication variant in TP53, NM_000546.6:dup(ex2-5), in a young triple-negative breast cancer patient. We aimed to assign its pathogenicity. METHODS: DNA and RNA (cDNA) level specific amplification tests and sequencings were performed to identify the genomic duplication breakpoint and to detect the presence of defective transcripts. RESULTS: cDNA tests revealed aberrant transcript, which causes a shift in the reading frame. Allelic imbalance was also observed, indicating degradation of the defective RNA product. By locating the breakpoints at the DNA level, we determined that 6975 bp was repeated in tandem and in the same orientation. We also revealed the possible mechanism of the structural rearrangement. CONCLUSIONS: We established that the duplication identified at DNA level manifested in the mRNA and coded for a non-functional protein. Based on these data, we were able to classify this duplication variant as pathogenic, which affects the patient's therapeutic options and justifies genetic screening of family members.

Adult↗

PubMed2026

Parental Perspectives and Experiences with Genetic Testing and Surveillance for Cancer Predisposition in Healthy Young Children.

OBJECTIVES: To evaluate parental experiences following diagnosis of a cancer predisposition syndrome (CPS) in childhood and to assess parental perspectives on population-based genomic newborn screening (gNBS) for CPS. STUDY DESIGN: Participants were guardians of children diagnosed with a CPS by age 8, for whom cancer surveillance was recommended, and who had no history of cancer before the CPS diagnosis. Participants completed a demographic survey, genetic knowledge assessment, and a semistructured qualitative interview. Thematic analysis was performed on interview transcripts. Clinical data were abstracted from medical records. RESULTS: We enrolled 25 parents of children with 7 different CPS, including Li-Fraumeni syndrome (43%), familial adenomatous polyposis (14%), nevoid basal cell carcinoma syndrome (11%), and Beckwith-Wiedemann syndrome (11%). Parents characterized receiving a CPS diagnosis as emotionally challenging but also felt empowered by engagement in proactive cancer surveillance. They identified logistical, emotional, physical, and financial burdens of surveillance; however, most perceived that these burdens were outweighed by the medical and emotional advantages. The majority endorsed implementation of gNBS for pediatric cancer risk. CONCLUSIONS: Parents of presymptomatic children with a CPS experience both psychological distress and benefits following a genetic diagnosis. Despite the burdens of surveillance, parents express support for early genomic identification of cancer risk. These findings have implications for the care of children with CPS and inform implementation of population-based gNBS for CPS.

Humans↗

PubMed2026

Non-invasive screening in hereditary cancer: a randomized controlled trial to test cell-free DNA-based early detection in the CHARM consortium.

Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with intensive surveillance to facilitate early cancer detection. However, participating in diagnostic imaging and endoscopy surveillance programs is often time-consuming, overwhelming, inconvenient, and anxiety-inducing. To improve this, multi-cancer early detection tests are being developed using cell-free DNA (cfDNA) sequencing analysis to detect cancers with more sensitivity than conventional screening methods. Our community (the CHARM consortium: Cell-free DNA in Hereditary And high-Risk Malignancies) has been exploring the use of cfDNA sequencing in hereditary cancer, and has launched the CHARM2 prospective randomized controlled trial, which is enrolling 1000 participants with Hereditary Breast and Ovarian Cancer, Lynch syndrome, Li-Fraumeni syndrome, Neurofibromatosis type 1 and Hereditary Diffuse Gastric Cancer to improve equitable access, early detection and surveillance for high-risk individuals. All participants will have screening as per conventional syndrome-specific surveillance recommendations. Half the participants (experimental cohort) will also have cfDNA analysis at least three times a year, with abnormal results triggering dedicated clinical imaging and diagnostic evaluation, and heightened surveillance. Vetted by our patient advisors, validated patient-reported outcome and experience measures assessing participant psychosocial outcomes, engagement, and test preferences will be administered to both arms. Our goal is to inform if and how cfDNA analysis could be implemented into routine clinical care and offer a path to equitable and more convenient cancer screening for all high-risk Canadians.

Female↗