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<p>Germline <i>TP53</i> pathogenic or likely pathogenic variants underlie Li–Fraumeni syndrome (LFS), but with broader use of multigene panel (MGP) testing, carriers are increasingly identified outside classic criteria. We retrospectively studied 36 carriers from 18 families evaluated at two Spanish hereditary cancer units (2005–2023). Clinical data were obtained from medical records, and variants were functionally classified using the Giacomelli model and IARC thresholds as dominant-negative with loss of function (DNE_LOF), non-dominant-negative without loss of function (noDNE_noLOF), non-dominant-negative with loss of function, or not assessed. Descriptive statistics summarized the tumor spectrum and group comparisons were performed using the Mann–Whitney U test (α = 0.05). Overall, 23 of 36 carriers (63.9%) developed at least one malignancy; 58.3% were female and the median age at first cancer was 36 years (range 27–54). Patients identified through MGP testing had later onset compared with those meeting clinical LFS criteria (median 42 [37–58] versus 27 [4–30] years; <i>p</i> = 0.011). Breast cancer was the most frequent tumor (65% of first cancers, median age 37 [30–47]), whereas none of the MGP-ascertained carriers developed LFS “core” tumors (sarcoma, brain tumor, adrenocortical carcinoma). Fifteen distinct germline variants were identified; 80% were missense, mainly in exons 5–8. DNE_LOF (median 30 [25–38.5]) were associated with earlier onset compared with noDNE_noLOF (47 [37–63]; <i>p</i> = 0.034). Eight carriers (34.7%) developed second primaries after a median interval of 6 years, and four developed third primaries. Functional classification may contribute to risk stratification; however, these findings are exploratory and hypothesis-generating, and require validation in larger prospective cohorts.</p>

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Genotypic and phenotypic characteristics of germline TP53 variant carriers: experience from two cancer genetic counseling units

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Beatriz Grau Mirete,
  • Asia Ferrández Arias,
  • Paula Rodríguez Payá,
  • María Valero Revert,
  • David Sánchez Garcia,
  • Mariano Martínez Marín,
  • Javier-David Benítez-Fuentes,
  • Isabel Chirivella González,
  • Ana Beatriz Sánchez Heras

摘要

Germline TP53 pathogenic or likely pathogenic variants underlie Li–Fraumeni syndrome (LFS), but with broader use of multigene panel (MGP) testing, carriers are increasingly identified outside classic criteria. We retrospectively studied 36 carriers from 18 families evaluated at two Spanish hereditary cancer units (2005–2023). Clinical data were obtained from medical records, and variants were functionally classified using the Giacomelli model and IARC thresholds as dominant-negative with loss of function (DNE_LOF), non-dominant-negative without loss of function (noDNE_noLOF), non-dominant-negative with loss of function, or not assessed. Descriptive statistics summarized the tumor spectrum and group comparisons were performed using the Mann–Whitney U test (α = 0.05). Overall, 23 of 36 carriers (63.9%) developed at least one malignancy; 58.3% were female and the median age at first cancer was 36 years (range 27–54). Patients identified through MGP testing had later onset compared with those meeting clinical LFS criteria (median 42 [37–58] versus 27 [4–30] years; p = 0.011). Breast cancer was the most frequent tumor (65% of first cancers, median age 37 [30–47]), whereas none of the MGP-ascertained carriers developed LFS “core” tumors (sarcoma, brain tumor, adrenocortical carcinoma). Fifteen distinct germline variants were identified; 80% were missense, mainly in exons 5–8. DNE_LOF (median 30 [25–38.5]) were associated with earlier onset compared with noDNE_noLOF (47 [37–63]; p = 0.034). Eight carriers (34.7%) developed second primaries after a median interval of 6 years, and four developed third primaries. Functional classification may contribute to risk stratification; however, these findings are exploratory and hypothesis-generating, and require validation in larger prospective cohorts.