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The risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li–Fraumeni syndrome (LFS) or Li–Fraumeni Like (LFL) patients. However, the type of TP53 pathogenic germline variant may possibly influence this risk. TP53 p.R337H mutation is particularly prevalent in Brazil. We aimed to evaluate the outcomes of patients with pathogenic TP53 variants treated for localized breast cancer in a Brazilian cohort. We evaluated retrospectively a cohort of patients with germline TP53 pathogenic variants treated for localized breast cancer between December 1999 and October 2017. All patients were followed by the Hereditary Cancer Group of an academic cancer center. Our primary objective was to evaluate the occurrence of RIMs after adjuvant radiotherapy. Sixteen patients were evaluated; 10 (62.5%) had a germline TP53 p.R337H pathogenic variant. Median age was 39.8 years. Thirteen patients had invasive ductal carcinoma: 8 (61.5%) were hormone receptor-positive; 6 (46.1%), human epithelial growth factor receptor 2 (HER2)-amplified. Three patients had ductal carcinoma in situ. Most patients (N = 12/16, 75%) received adjuvant radiotherapy. After a median follow-up of 52.5 months, 2 patients (2/12, 16.6%) had RIMs. One had a fibrosarcoma and the other, a low-grade leiomyosarcoma. In the group treated with radiotherapy, one distant recurrence was diagnosed (1/12), and no loco-regional recurrence occurred. Among 4 patients who did not receive radiotherapy, 2 presented with loco-regional recurrence. In this cohort of patients with LFS enriched in TP53 p.R337H pathogenic variant, the incidence of RIMs after treatment of localized breast cancer was lower than previous literature. Nevertheless, rates of RIMs were still alarming. Early molecular diagnosis and careful evaluation of treatment risks and benefits are essential for these patients.

We evaluated the prevalence of pathogenic/likely pathogenic germline variants (PGV) in Brazilian pancreatic adenocarcinoma (PC) patients, that represent a multiethnic population, in a cross-sectional study. We included 192 PC patients unselected for family history of cancer. We evaluated a panel of 113 cancer genes, through genomic DNA sequencing and 46 ancestry-informative markers, through multiplex PCR. The median age was 61 years; 63.5% of the patients presented disease clinical stages III or IV; 8.3% reported personal history of cancer; 4.7% and 16.1% reported first-degree relatives with PC or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Twelve patients (6.25%) were PGV carriers in PC predisposition genes ( ATM , BRCA1 , BRCA2 , CDKN2A , MSH2 , PALB2 ) and another 25 (13.0%) were PGV carriers in genes with a limited association or not previously associated with PC ( ACD , BLM , BRIP1 , CHEK2 , ERCC4 , FANCA , FANCE , FANCM , GALNT12 , MITF , MRE11 , MUTYH , POLE , RAD51B , RAD51C , RECQL4 , SDHA , TERF2IP) . The most frequently affected genes were CHEK2 , ATM and FANC . In tumor samples from PGV carriers in ACD , BRIP1 , MRE11 , POLE , SDHA , TERF2IP , which were examined through exome sequencing, the main single base substitutions (SBS) mutational signature was SBS1+5+18, probably associated with age, tobacco smoking and reactive oxygen species. SBS3 associated with homologous repair deficiency was also represented, but on a lower scale. There was no difference in the frequency of PGV carriers between: (a) patients with or without first-degree relatives with cancer; and (b) patients with admixed ancestry versus those with predominantly European ancestry. Furthermore, there was no difference in overall survival between PGV carriers and non-carriers. Therefore, genetic testing should be offered to all Brazilian pancreatic cancer patients, regardless of their ancestry. Genes with limited or previously unrecognized associations with pancreatic cancer should be further investigated to clarify their role in cancer risk.

Abstract Disclosure: M.B. Lacerda: None. M. Buchpiguel: None. M. Sousa: None. L. Pimentel: None. L. Leite: None. M.Q. Almeida: None. M. Ferreira: None. M.F. Funari: None. A. Latronico: None. A.O. Hoff: None. B.B. Mendonca: None. M. Diz: None. M. Fragoso: None. Introduction: Li-Fraumeni Syndrome (LFS) is an autosomal dominant hereditary condition caused by pathogenic variants (PVs) in the TP53, which predisposes individuals to early-onset tumors. The germline p.R337H variant is particularly prevalent in Brazil, especially in the South and Southeast regions. Diagnosis is based on the Chompret Criteria {(1. An individual with a tumor belonging to the LFS spectrum before the age of 46 AND At least one first- or second-degree relative with a tumor associated with LFS (except breast cancer if the index case had breast cancer) before the age of 56 OR with multiple tumors OR 2. An individual with multiple tumors (except breast), two of which belong to the LFS spectrum, and the first of them occurred before the age of 46 OR 3. An individual with adrenocortical carcinoma or choroid plexus tumor, regardless of family history.)}. This study evaluates the application of these criteria in LFS. Objective: to analyze clinical and diagnostic data related to TP53 p.R337H variant both retrospectively and prospectively. The secondary objective was to assess the effectiveness of the Chompret Criteria in identifying individuals at increased risk of developing LFS. Subjects and Methods: This study included patients treated at tertiary centers between 2002 and 2024 who met the Chompret Criteria and underwent TP53 gene sequencing. Clinical, epidemiological, and laboratory data were obtained. The study was approved by the local Ethics Committee, and informed consent was obtained. Results: A total of 381 index cases were analyzed. Among these, 107 cases (28%) had TP53 PV, with 77 (72%) identified as carriers of the p.R337H variant. The distribution of Chompret Criteria among p.R337H carriers was as follows: Criterion 1 (25.97%), Criterion 2 (7.79%), and Criterion 3 (66.23%), being the most effective for screening. Carriers of the p.R337H PV were predominantly female (77%), with a mean age of 33 years at diagnosis, and were predominantly from the Southeast region (95%), particularly from the states of São Paulo (79.22%) and Minas Gerais (15.6%). Among p.R337H carriers, the primary tumor sites were adrenal gland (63.52%), breast (23.52%), and soft tissues (7.05%). The most frequent histopathological diagnoses were pediatric adrenal tumors (41.2%), adrenocortical carcinoma (21.2%), and invasive ductal carcinoma of the breast (15.3%). The mortality rate among carriers was 29.9%. Discussion/Conclusion: The Chompret Criteria, particularly Criterion 3, proved highly effective in identifying patients carrying the p.R337H variant. The high prevalence of the p.R337H PV among patients from Southeast Brazil, associated with primary tumors, highlights the need for effective surveillance strategies and early diagnosis, supporting genetic screening in at-risk populations. Presentation: Sunday, July 13, 2025