Clinical and genetic characteristics of carriers of the TP53 c.541C > T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent

TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 ( TP53 ): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospective...

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Bibliographic Details
Published in:	Familial cancer Vol. 23; no. 4; pp. 531 - 542
Main Authors:	Arnon, Johnathan, Zick, Aviad, Maoz, Myriam, Salaymeh, Nada, Gugenheim, Ahinoam, Marouani, MazalTov, Mor, Eden, Hamburger, Tamar, Saadi, Nagam, Elia, Anna, Ganz, Gael, Fahham, Duha, Meirovitz, Amichay, Kadouri, Luna, Meiner, Vardiella, Yablonski-Peretz, Tamar, Shkedi-Rafid, Shiri
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer Netherlands 01-11-2024 Springer Nature B.V
Subjects:	Adolescent Adult Aged Arabs - genetics Biomedical and Life Sciences Biomedicine Cancer Cancer Research Carcinogens Child Child, Preschool Choroid plexus Demography Epidemiology Exome Sequencing Female Genetic Predisposition to Disease Genetic screening Genetic Testing Glioblastoma Haplotypes Heterozygote Human Genetics Humans Infant Israel Li-Fraumeni syndrome Li-Fraumeni Syndrome - genetics Male Malignancy Medulloblastoma Middle Aged Neoplasms - genetics Original Original Article p53 Protein Patients Pediatrics Pedigree Phenotypes Population genetics Retrospective Studies Tumor Suppressor Protein p53 - genetics Whole genome sequencing Young Adult Israel Jerusalem Israel p.Arg181Cys Arab-Muslim Hereditary cancer syndrome Li-Fraumeni TP53
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Summary:	TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 ( TP53 ): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1–69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2–54)—19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1389-9600 1573-7292 1573-7292
DOI:	10.1007/s10689-024-00391-2