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

Abstract

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.

Keywords: TP53; Arab-Muslim; Hereditary cancer syndrome; Li-Fraumeni; p.Arg181Cys.

Fig. 1

Flow chart of genetic testing conducted between 2005 and 2022 at Hadassah Medical Center and identification of carriers of TP53 p.Arg181Cys variant

Fig. 2

Examples of five pedigrees including six probands (black arrow) of carriers of TP53 p.Arg181Cys showing variable family history of malignancy. Ages listed are age at cancer diagnosis or age of last follow up in case of healthy carrier

Fig. 3

Haplotype analysis of TP53 p.Arg181Cys. Using whole exome sequencing on DNA sample of one patient homozygous for the TP53 p.Arg181Cys variant we identified a mutual homozygous region in the relevant chromosomal region of TP53 spanning at least 350kb which was determined as the obligatory haplotype. TP53 sequenced results from the additional TP53 p.Arg181Cys carriers (8 cancer patients from 8 families and 13 healthy carriers from 9 families) found this region to be shared among all carriers tested. The locations of the 7 SNPs comprising the haplotype depicted are outlined below: rs4968189:Chr17(GRCh37):g.7460559 T > G; rs74336587: Chr17(GRCh37):g.7489417 C > T; rs1642763: Chr17(GRCh37):g.7557419 A > G; rs1042522: Chr17(GRCh37):g.7579472 G > C located on the p.Arg72 allele of TP53; rs2287499: Chr17(GRCh37):g.7592168 C > G; rs9909288: Chr17(GRCh37):g.7673928 C > G; rs4239111: Chr17(GRCh37):g.7811998 T > C