The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort.

Autor: Abu Shtaya A; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel.; Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel., Kedar I; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Mattar S; Department of Surgery B, Carmel Medical Center, Haifa 3436212, Israel., Mahamid A; Department of Surgery B, Carmel Medical Center, Haifa 3436212, Israel., Basel-Salmon L; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.; Felsenstein Medical Research Center, Petach Tikva 4920235, Israel.; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petch Tikva 49202, Israel., Farage Barhom S; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Naftaly Nathan S; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Magal N; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Azulay N; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Levy Zalcberg M; Genetics Institute, Soroka Medical Center, Beer Sheva 84101, Israel., Chen-Shtoyerman R; Adelson School of Medicine, Department of Molecular Biology, Ariel University, Ariel 40700, Israel.; Kaplan Medical Center, Genetics Institute, Oncogenetic Clinic, Rehovot 7610001, Israel., Segol O; Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel., Seri M; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Reznick Levi G; Genetics Institute, Rambam Health Care Campus, Haifa 31096, Israel., Shkedi-Rafid S; Department of Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel., Vinkler C; Institute for Medical Genetics, Wolfson Medical Center, Holon 5822012, Israel., Netzer I; Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel., Hagari Bechar O; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Chamma L; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel., Liberman S; Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 9112102, Israel., Goldberg Y; Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Dec 24; Vol. 16 (1). Date of Electronic Publication: 2023 Dec 24.
DOI: 10.3390/cancers16010094
Abstrakt: Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020-January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.
Databáze: MEDLINE
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