BACKGROUND AND OBJECTIVE:BRCA1 and BRCA2 pathogenic germline variants (PGVs) are associated with higher risk of prostate cancer (PC). The IMPACT study evaluated the utility of targeted prostate-specific antigen (PSA) screening in BRCA1/BRCA2 PGV carriers. Here we report outcomes after five rounds of PSA screening in IMPACT. METHODS:Between 2005 and 2015, 3063 participants aged 40-69 yr (median 54 yr) were recruited from 65 centres in 20 countries in two cohorts: (1) BRCA1/BRCA2 PGV carriers (915 BRCA1, 901 BRCA2); and (2) age-matched noncarriers for a familial PGV (727 BRCA1 and 520 BRCA2 noncarriers). Annual PSA screening was performed, with PSA >3.0 ng/ml used as the indication for prostate biopsy. Our aim was to identify differences by PGV status in (1) the incidence of PC and of clinically significant PC (csPC; grade group ≥2) and (2) tumour stage and characteristics after five screening rounds. KEY FINDINGS AND LIMITATIONS:There was no statistically significant difference in PC incidence between BRCA1/BRCA2 PGV carriers and noncarriers. csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017). There were no T4 or metastatic PC cases. Pathology after radical prostatectomy revealed tumour upgrading for 7/23 (26%) BRCA1 PGV carriers and 10/34 (26%) BRCA2 PGV carriers, with no tumour upgrading for men without PGVs. Study limitations include the biopsy compliance rate and changes in PC diagnostic pathways since 2005. CONCLUSIONS AND CLINICAL IMPLICATIONS:Annual PSA screening in BRCA2 PGV carriers confirmed a higher incidence of csPC and detection of clinically relevant tumours in comparison to noncarriers. For the first time, we confirm that PSA screening in BRCA1 PGV carriers results in early detection of NCCN IR-U/HR PC. Systematic PSA screening is recommended for BRCA2 PGV carriers and should be considered for BRCA1 PGV carriers.

Supplementary Table S1: Reported cases of individuals with germline hypomorphic TP53 variants

Abstract In individuals with classic Li-Fraumeni syndrome (LFS) due to a loss-of-function pathogenic germline variant in TP53, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adrenal cortical carcinomas, brain tumors, and leukemia. In adults with classic LFS, in addition to the classical malignancies, breast cancers and other cancers develop at earlier ages of onset compared with individuals without LFS. Increased genetic testing is identifying a higher frequency of germline TP53 variants with conflicting interpretations in clinical databases, some of which are likely hypomorphic or of atypical penetrance. Studies of these hypomorphic TP53 variants reveal differential retention or loss of the myriad of p53 tumor-suppressive functions. Many individuals with hypomorphic TP53 variants develop cancer, including both canonical and common types, though at later ages compared with classic LFS. Therefore, further study is needed to understand the most critical tumor suppressive functions of p53, as are data-driven clinical guidelines for the management of cancer risk. Herein, we review models of TP53 variant classification, focusing on strategies to identify hypomorphic TP53 variants. We go on to review the biology and clinical phenotypes of TP53 hypomorphic variants that have detailed reports of their effects on p53 tumor-suppressive functions. Using this framework, we propose possible modifications to the standard LFS screening protocol for individuals with hypomorphic TP53 variants that should be studied in prospective clinical trials.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

OBJECTIVES:Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome that may confer increased pancreatic cancer (PC) risk. This study assesses PC risk and the rate of pancreatic imaging abnormalities in LFS. METHODS:PC prevalence in LFS was calculated for individuals with a known TP53 variant from the IARC/NCI database. Pancreatic imaging studies across 3 institutional LFS cohorts were reviewed and compared using the Fisher exact test. RESULTS:Of 3043 individuals with LFS in the IARC/NCI database, 46 (1.5%) had PC, and 42/1243 (3.4%) LFS families had a member with PC. Among PCs with a known age of diagnosis, 2.6% and 43.2% were diagnosed before age 30 and 50, respectively. Across 3 institutional LFS cohorts, 32/329 (9.7%) individuals had a pancreatic imaging abnormality, including cysts in 20 (6.1%) and a mass in 4 (1.2%). Whole-body MRI (WBMRI) had the lowest detection rate of pancreatic abnormalities (6%), whereas endoscopic ultrasound (EUS)/MRI abdomen (MRI Abd) had the highest (50% and 20.8%, respectively). Cysts were detected more frequently with EUS/MRI Abd (33.1% and 18.1%, respectively) compared with WBMRI (4.3%). Individuals older than age 50 were more likely to have a pancreatic abnormality (35.8% vs. 4.7%, P <0.01) or pancreatic cyst (26.4% vs. 2.2%, P <0.001) compared with those younger than age 50. CONCLUSIONS:PC may occur earlier in LFS compared with the general population. WBMRI identifies pancreatic abnormalities less frequently than other pancreatic cancer screening modalities in LFS. If dedicated PC screening is performed in LFS, screening should likely start before age 50 and use either EUS or MRI Abd.

BRIP1 (OMIM: 605882), associated with hereditary ovarian cancer, has recently been described in association with central nervous system (CNS) tumours. Institutional germline database review identified 43 families with BRIP1 pathogenic germline variants (PGVs); 7 families (16.3%) reported 8 CNS tumours. Somatic database review identified 1143 individuals with CNS tumours who underwent somatic sequencing, of whom 7 had BRIP1 pathogenic variants (PVs) (0.6%); 1 of 2 germline-tested individuals had a BRIP1 PGV. Though BRIP1 PVs are rare in CNS tumours, a substantial proportion of BRIP1 carriers have a positive family history. Obtaining and documenting the clinical and pathological characteristics of reported CNS tumours in BRIP1 individuals and families is key to exploring a possible association.

Purpose Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited. Methods Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES. Results Average frequencies of heterozygotes with PGVs across ancestries for BRCA1 and BRCA2 were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. ATM had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and SDHD the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data. Discussion Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples’ reproductive risk planning.

Background/Purpose: Iron deficiency (ID) with or without anemia is a prevalent health problem. Iron deficiency anemia (IDA) affects at least 1.2 billion individuals worldwide, and iron deficiency without anemia (IDWA) is at least twice as common. The WHO uses a serum ferritin <15 mcg/L to define ID in adults. While this threshold might be specific for ID, it has been criticized for potentially leading to underdiagnosis of the condition. The present study aims to systematically review the literature on the prevalence of ID with and without anemia in adults older than 18 years based on serum ferritin thresholds of 15, 30, and 50 mcg/L. Methods: As part of the new American Society of Hematology guidelines on the diagnosis of iron deficiency (ID) with or without anemia, we searched the published literature in PubMed, Embase, and The Cochrane Central Register of Controlled Trials from inception until January 2025. Two reviewers independently screened the studies to assess their eligibility using Covidence systematic review software (Australia). A study was included if it reported the prevalence of ID in adults, used serum ferritin with a prespecified cutoff, and had a sample size of more than 1000. We statistically combined estimates using Stata 19 using the inverse-variance common-effect model. Reviewers assessed the risk of bias using a risk of bias tool assessing three domains: sampling, condition definition, and statistical analysis. Results: After screening 26,717 references, a total of 71 eligible studies (n=527,746) were included. Of these, 57 studies (n = 399,242) used a ferritin threshold <15 mcg/L, 26 used a ferritin threshold of <30 mcg/L, and 3 (n = 91,299) used a ferritin threshold of <50 mcg/L. The overall statistically pooled prevalence of ID across all thresholds was 30% (95% CI: 29–30%). At a ferritin threshold of <15 mcg/L, the pooled prevalence of ID was 11% (95% CI: 11–11%). Subgroup analysis based on sex and state of menopause revealed a prevalence of 5% (95% CI: 5–5%) in males (n=92,005), 19% (95% CI: 19–20%) in pre-menopausal females (n=95,619), and 5% (95% CI: 5–6) in females post menopause (n=21,884). At a ferritin threshold of <30 mcg/L, the statistically pooled prevalence of ID was 31% (95% CI: 31–31%). Subgroup analysis showed a prevalence of 20% (95% CI: 19–20%) in males (n= 74,593), 49% (95% CI: 49–50) in premenopausal females (n=115,212), and 18% (95% CI: 16–19%) in females post menopause (n=2,666),. At a ferritin threshold of <50 ng/mL, the prevalence of ID was 37% (95% CI: 37–37%). Subgroup analysis showed a prevalence of 40% (95% CI: 39–42%) in males (n=3,632), 70% (95% CI: 70–71%) among premenopausal females (n=8,846), and 49% (48% to 50%) in females post menopause (n=5,916). Conclusion: ID with or without anemia is highly prevalent among adults, with substantial differences depending on the ferritin cutoff used. At the WHO-recommended cutoff of <15 mcg/L, the prevalence of ID is relatively low, particularly among males and females postmenopause. However, using higher thresholds of <30 or <50 mcg/L reveals a substantially higher prevalence, especially in premenopausal females, in which over half the population would meet criteria for ID. These findings suggest that currently endorsed thresholds might lead to underestimating the true burden of ID with or without anemia and highlight the importance of considering higher ferritin cutoffs for more sensitive detection.

BackgroundGermline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.Patients and MethodsRetrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.ResultsTwenty-one of 125 unrelated probands (17%) were found to harbor a TP53 PV with VAF<30% or a designation of “mosaic”. A diagnosis of PZM was made in nine (43%) due to a clinical phenotype consistent with LFS with (n=8) or without (n=1) positive ancillary tissue testing. Twelve patients (57%) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.ConclusionsDetermining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.

Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children’s Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the “My Bibliography” tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. Results: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. Conclusions: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.

Pintotable1.xlsx Table S1a. Cohort characteristicsTable S1b. Frequencies and features of TP53 variants at codon 125 in public databasesTable S1c. Annotation and interpretation of TP53 variants at codon 125 and surrounding basesTable S1d. Splice site predictionTable S1e. Primers sequences for mutagenesis constructs and cDNA sequencing Table S1f. STR profiling of Saos-2 and H1299 cell lines

Supplementary Figure 2 PDF file 78K, This figure depicts the assay used to visualize repair proteins at DNA double-strand breaks

Abstract Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%–4% initial, 6%–10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes. Prevention Relevance: The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.

PURPOSE:We developed a web-based education intervention as an alternative to predisclosure education with a genetic counselor (GC) to reduce participant burden and provider costs with return of genetic research results. METHODS:Women at three sites who participated in 11 gene discovery research studies were contacted to consider receiving cancer genetic research results. Participants could complete predisclosure education through web education or with a GC. Outcomes included uptake of research results, factors associated with uptake, and patient-reported outcomes. RESULTS:Of 819 participants, 178 actively (21.7%) and 167 passively (20.4%) declined return of results; 474 (57.9%) were enrolled. Most (60.3%) received results although this was lower than the 70% uptake we hypothesized. Passive and active decliners were more likely to be Black, to have less education, and to have not received phone follow-up after the invitation letter. Most participants selected web education (88.5%) as an alternative to speaking with a GC, but some did not complete or receive results. Knowledge increased significantly from baseline to other time points with no significant differences between those who received web versus GC education. There were no significant increases in distress between web and GC education. CONCLUSION:Interest in web-based predisclosure education for return of genetic research results was high although it did not increase uptake of results. We found no negative patient-reported outcomes with web education, suggesting that it is a viable alternative delivery model for reducing burdens and costs of returning genetic research results. Attention to attrition and lower uptake of results among Black participants and those with less formal education are important areas for future research.

Supplementary Figures 1-4. Supplementary Figure S1: Full Pedigrees from TP53 c.1000G>C;p.G334R clinically ascertained families. Fam ID allows reference to Table 1; Supplementary Figure S2: Constructs encoding p53 wild-type (TP53-WT), p53-R175H (TP53-R175H), and p53-G334R (c.1000G>A and c.1000G>C) were transiently transfected into p53 deficient Saos-2 cells; Supplementary Figure S3: p53 levels after treatment with 10uM cisplatin (CDDP); Supplementary Figure S4: Heatmap showing fold activation of a canonical p53 signature at 24 hours post nutlin with wildtype versus mutant lymphoblastoid cell lines.