Germline variants in patients from the Iranian hereditary colorectal cancer registry

被引：0

作者：

Goshayeshi, Lena ^{[1
,2
]}

Hoorang, Saeed ^{[3
]}

Hoseini, Benyamin ^{[4
]}

Abbaszadegan, Mohammad Reza ^{[5
]}

Afrazeh, Maryam ^{[6
]}

Alimardani, Maliheh ^{[5
]}

Maghool, Fatemeh ^{[7
]}

Shademan, Milad ^{[8
]}

Zahedi, Morteza ^{[2
]}

Zeinalian, Mehrdad ^{[9
]}

Alborzi, Foroogh ^{[10
]}

Keramati, Mohammad Reza ^{[11
]}

Torshizian, Ashkan ^{[12
]}

Vosoghinia, Hassan ^{[13
]}

Rajabzadeh, Farnood ^{[14
]}

Bary, Alireza ^{[15
]}

Bahar, Massih ^{[16
]}

Javadmanesh, Ali ^{[17
,18
]}

Sorouri-Khorashad, Jamshid ^{[19
]}

Emami, Mohammad Hassan ^{[7
]}

Daryani, Nasser Ebrahimi ^{[10
]}

Vasen, Hans F. A. ^{[20
]}

Goshayeshi, Ladan ^{[1
,13
]}

Dehghani, Hesam ^{[2
,21
]}

机构：

[1] Mashhad Univ Med Sci, Imam Reza Hosp, Fac Med, Surg Oncol Res Ctr, Mashhad, Iran

[2] Ferdowsi Univ Mashhad, Res Inst Biotechnol, Stem Cell Biol & Regenerat Med Res Grp, Azadi Sq, Mashhad 9177948974, Iran

[3] Abu Ali Sina Hosp, Dept Gastroenterol & Hepatol, Shiraz, Iran

[4] Mashhad Univ Med Sci, Pharmaceut Technol Inst, Pharmaceut Res Ctr, Mashhad, Iran

[5] Mashhad Univ Med Sci, Fac Med, Dept Med Genet, Mashhad, Iran

[6] Mashhad Univ Med Sci, Fac Med, Dept Gastroenterol & Hepatol, Mashhad, Iran

[7] Isfahan Univ Med Sci, Poursina Hakim Digest Dis Res Ctr, Esfahan, Iran

[8] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[9] Isfahan Univ Med Sci, Sch Med, Dept Genet & Mol Biol, Esfahan, Iran

[10] Univ Tehran Med Sci, Dept Gastroenterol & Hepatol, Tehran, Iran

[11] Univ Tehran Med Sci, Fac Med, Dept Surg, Div Colorectal Surg, Tehran, Iran

[12] Mashhad Univ Med Sci, Fac Med, Mashhad, Iran

[13] Mashhad Univ Med Sci, Fac Med, Dept Gastroenterol & Hepatol, Mashhad, Iran

[14] Islamic Azad Univ, Dept Radiol, Mashhad Branch, Mashhad, Iran

[15] Mashhad Univ Med Sci, Sch Med, Hematol Oncol Dept, Mashhad, Iran

[16] Familial & Hereditary Canc Inst, Tehran, Iran

[17] Ferdowsi Univ Mashhad, Fac Agr, Dept Anim Sci, Mashhad, Iran

[18] Ferdowsi Univ Mashhad, Res Inst Biotechnol, Ind Biotechnol Res Grp, Mashhad, Iran

[19] Royal Marsden Hosp, Ctr Mol Pathol, Inst Canc Res, London, England

[20] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Leiden, Netherlands

[21] Ferdowsi Univ Mashhad, Fac Vet Med, Dept Basic Sci, Mashhad, Iran

来源：

CANCER CELL INTERNATIONAL | 2025年 / 25卷 / 01期

关键词：

Hereditary colorectal Cancer; Germline variants; Whole exome sequencing (WES); Lynch syndrome; Polyposis syndrome; LYNCH-SYNDROME; PREDISPOSITION GENES; PATHOGENIC VARIANTS; MUTATIONS; SUSCEPTIBILITY; INDIVIDUALS; PREVALENCE; GUIDELINES; CYTOSCAPE; HMSH6;

D O I：

10.1186/s12935-025-03773-3

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background and aimHereditary 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.MethodsWhole 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.ResultsPathogenic/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.ConclusionsThe 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.

引用

页数：13

共 54 条

[11] Cytoscape StringApp: Network Analysis and Visualization of Proteomics Data [J].