Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel

• Type of Material: Article
• Authors: Malak AlThgafi, Emory University; Musa AlHarbi, King Fahad Medical City; Nahla A Mobark, King Fahad Medical City; Wael Abdel Rahman AlJabarat, King Fahad Medical City; Hadeel ElBardis, King Fahad Medical City; Ebtehal AlSolme, King Fahad Medical City; Abdullah B Hamdan, King Fahad Medical City; Ali H AlFakeeh, King Fahad Medical City; Fatimah AlMushawah, King Fahad Medical City; Fawz AlHarthi, King Fahad Medical City; Abdullah A AlSharm, King Fahad Medical City; Ali Abdullah O Balbaid, King Fahad Medical City; Naji AlJohani, King Fahad Medical City; Alicia Y Zhou, Color Health Inc; Heather A Robinson, The University of Manchester; Saleh A Alqahtani, Johns Hopkins University; Malak Abedalthagafi, King Fahad Medical City
• Language: English
• Date: 2023-06-01
• Publisher: Impact Journals, LLC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 AlHarbi et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.28457
• Title of Journal or Parent Work: Oncotarget
• Volume: 14
• Start Page: 580
• End Page: 594
• Grant/Funding Information: This study was supported by King Fahad Medical City MA and MAA (RFA17-17). The funding body was not involved in any stage of the study and had no role in the design of the study, the collection, analysis, and interpretation of data or the writing of the manuscript.
• Keywords: Genetic Predisposition to Disease; cancer screening; Nasopharyngeal Neoplasms; Colorectal Neoplasms; High-Throughput Nucleotide Sequencing; Prevalence; NGS; hereditary cancer syndrome; genetic counseling; cancer; Saudi Arabia; Humans
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.