Cancer Cell International, Volume (25), No (1), Year (2025-4)

Title : ( Germline variants in patients from the Iranian hereditary colorectal cancer registry )

Authors: Lena Goshayeshi , Saeed Hoorang , Benyamin Hoseini , Mohammad Reza Abbaszadegan , Maryam Afrazeh , Maliheh Alimardani , Fatemeh Maghool , Milad Shademan , Morteza Zahedi , Mehrdad Zeinalian , Foroogh Alborzi , Mohammad Reza Keramati , Ashkan Torshizian , Hassan Vosoghinia , Farnood Rajabzadeh , Alireza Bary , Massih Bahar , Ali Javadmanesh , Jamshid Sorouri-Khorashad , Mohammad Hassan Emami , Nasser Ebrahimi Daryani , Hans F.A. Vasen , Ladan Goshayeshi , Hesam Dehghani ,

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Abstract

Background and aim Hereditary cancer syndromes account for 6–10% of all colorectal cancer (CRC) cases and 20% of early-onset CRC. Identifying novel pathogenic germline variants can impact genetic testing, counseling, and surveillance. This study aimed to determine the prevalence of germline variants associated with hereditary CRC in the Iranian population. Methods Whole exome sequencing (WES) was conducted on DNA from 101 patients in the Iranian Hereditary Colorectal Cancer Registry (IHCCR). The cohort included 63 high-risk Lynch Syndrome (LS) patients and 38 colorectal polyposis patients. Germline variants and phenotype spectrum were assessed. Relatives of individuals with the mutations received counseling and cascade testing. Gene ontology and protein-protein interaction (PPI) analyses were conducted to elucidate gene roles on protein function. Results Pathogenic/likely pathogenic (P/LP) variants were identified in Lynch-related genes in 36.51% of patients. P/LP variants in non-Lynch genes (ATM, FH (mono-allelic), MSH3, PMS1, and TP53) were identified in 26.98% of patients. Among polyposis patients, 50% had P/LP variants in the APC gene, and 15.79% had P/LP variants in the MUTYH gene. Additionally, 7.89% carried P/LP variants in non-FAP/MAP genes (BLM, BRCA2, and PTEN). MLH1 variants were most common in exons 10 and 18, MSH2 in exon 12, and APC gene in exon 16. Cascade testing identified 50% of the tested relatives (40/80). Topology analysis of the protein-protein interaction networks in high-risk LS cases highlighted stronger connections among nodes for genes such as TP53, ATM, POLD1, CDH1, MUTYH, WRN, NOTCH1, SMAD4, ERCC4, ERCC1, and MSH3. These genes were associated with high penetrance in CRC. The protein-protein interaction analyses of polyposis patients indicated that genes like POLE, MSH6, MSH2, BRCA2, BRCA1, MLH1, TOPBP1, BLM, RAD50, MUTYH, MSH3, MLH3, PTEN, BRIP1, and POLK had a higher degree value and were also associated with high penetrance. Gene ontology and protein-protein interaction (PPI) analysis showed that some of the top-scoring non-Lynch genes were TP53, ATM, POLD1, CDH1, MUTYH, WRN, NOTCH1, SMAD4, ERCC4, ERCC1, and MSH3. Conclusions The study identified crucial germline variants for hereditary polyposis and non-polyposis CRC pathogenesis in the Iranian population. A selective strategy and cascade genetic testing are recommended for the diagnosis of hereditary colorectal cancer syndromes.

Keywords

Hereditary colorectal Cancer Germline variants Whole exome sequencing (WES) Lynch syndrome Polyposis syndrome
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@article{paperid:1102962,
author = {لنا گشایشی and سعید هورنگ and بنیامین حسینی and محمدرضا عباس زادگان and مریم افرازه and ملیحه علیمردانی and فاطمه معقول and میلاد شادمان and Zahedi, Morteza and مهرداد زینعلیان and فروغ البرزی and محمدرضا کرامتی and اشکان ترشیزیان and حسن وثوقی نیا and فرنود رجب زاده and علیرضا باری and مسیح بهار and Javadmanesh, Ali and جمشید سروری-خراشاد and محمدحسن امامی and ناصر ابراهیمی دریانی and هانس واسن and لادن گشایشی and Dehghani, Hesam},
title = {Germline variants in patients from the Iranian hereditary colorectal cancer registry},
journal = {Cancer Cell International},
year = {2025},
volume = {25},
number = {1},
month = {April},
issn = {1475-2867},
keywords = {Hereditary colorectal Cancer Germline variants Whole exome sequencing (WES) Lynch syndrome Polyposis syndrome},
}

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%0 Journal Article
%T Germline variants in patients from the Iranian hereditary colorectal cancer registry
%A لنا گشایشی
%A سعید هورنگ
%A بنیامین حسینی
%A محمدرضا عباس زادگان
%A مریم افرازه
%A ملیحه علیمردانی
%A فاطمه معقول
%A میلاد شادمان
%A Zahedi, Morteza
%A مهرداد زینعلیان
%A فروغ البرزی
%A محمدرضا کرامتی
%A اشکان ترشیزیان
%A حسن وثوقی نیا
%A فرنود رجب زاده
%A علیرضا باری
%A مسیح بهار
%A Javadmanesh, Ali
%A جمشید سروری-خراشاد
%A محمدحسن امامی
%A ناصر ابراهیمی دریانی
%A هانس واسن
%A لادن گشایشی
%A Dehghani, Hesam
%J Cancer Cell International
%@ 1475-2867
%D 2025

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