Goshayeshi Lena, Hoorang Saeed, Hoseini Benyamin, Abbaszadegan Mohammad Reza, Afrazeh Maryam, Alimardani Maliheh, Maghool Fatemeh, Shademan Milad, Zahedi Morteza, Zeinalian Mehrdad, Alborzi Foroogh, Keramati Mohammad Reza, Torshizian Ashkan, Vosoghinia Hassan, Rajabzadeh Farnood, Bary Alireza, Bahar Massih, Javadmanesh Ali, Sorouri-Khorashad Jamshid, Emami Mohammad Hassan, Daryani Nasser Ebrahimi, Vasen Hans F A, Goshayeshi Ladan, Dehghani Hesam
Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974, Iran.
Cancer Cell Int. 2025 Apr 13;25(1):140. doi: 10.1186/s12935-025-03773-3.
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.
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.
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.
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.
遗传性癌症综合征占所有结直肠癌（CRC）病例的6 - 10%，占早发性CRC的20%。识别新的致病种系变异会影响基因检测、咨询和监测。本研究旨在确定伊朗人群中与遗传性CRC相关的种系变异的患病率。
对伊朗遗传性结直肠癌登记处（IHCCR）的101例患者的DNA进行全外显子测序（WES）。该队列包括63例高危林奇综合征（LS）患者和38例结直肠息肉病患者。评估种系变异和表型谱。有突变个体的亲属接受咨询和级联检测。进行基因本体论和蛋白质 - 蛋白质相互作用（PPI）分析以阐明基因对蛋白质功能的作用。
36.51%的患者在林奇相关基因中鉴定出致病/可能致病（P/LP）变异。26.98%的患者在非林奇基因（ATM、FH（单等位基因）、MSH3、PMS1和TP53）中鉴定出P/LP变异。在息肉病患者中，50%的患者在APC基因中有P/LP变异，15.79%的患者在MUTYH基因中有P/LP变异。此外，7.89%的患者在非FAP/MAP基因（BLM、BRCA2和PTEN）中携带P/LP变异。MLH1变异在外显子10和18中最常见，MSH2在外显子12中，APC基因在外显子16中。级联检测在50%的受测亲属（40/80）中发现了变异。高危LS病例中蛋白质 - 蛋白质相互作用网络的拓扑分析突出了TP53、ATM、POLD1、CDH1、MUTYH、WRN、NOTCH1、SMAD4、ERCC4、ERCC1和MSH3等基因的节点之间更强的连接。这些基因与CRC的高外显率相关。息肉病患者的蛋白质 - 蛋白质相互作用分析表明，POLE、MSH6、MSH2、BRCA2、BRCA1、MLH1、TOPBP1、BLM、RAD50、MUTYH、MSH3、MLH3、PTEN、BRIP1和POLK等基因具有更高的度值，也与高外显率相关。基因本体论和蛋白质 - 蛋白质相互作用（PPI）分析表明，一些得分最高的非林奇基因是TP53、ATM、POLD1、CDH1、MUTYH、WRN、NOTCH1、SMAD4、ERCC4、ERCC1和MSH3。
该研究确定了伊朗人群中遗传性息肉病和非息肉病性CRC发病机制的关键种系变异。建议采用选择性策略和级联基因检测来诊断遗传性结直肠癌综合征。
