WRN Germline Mutation Is the Likely Inherited Etiology of Various Cancer Types in One Iranian Family

Abstract

BackgroundFamilial cancers comprise a considerable distribution of colorectal cancers (CRCs), of which only about 5% occurs through well-established hereditary syndromes. It has been demonstrated that deleterious variants at the newly identified cancer-predisposing genes could describe the etiology of undefined familial cancers.MethodsThe present study aimed to identify the genetic etiology in a 32-year-old man with early onset familial CRC employing several molecular diagnostic techniques. DNA was extracted from tumoral and normal formalin-fixed-paraffin-embedded (FFPE) blocks, and microsatellite instability (MSI) was evaluated. Immunohistochemistry staining of MMR proteins was performed on tumoral FFPE blocks. Next-generation sequencing (NGS), multiplex ligation-dependent amplification (MLPA) assay, and Sanger sequencing were applied on the genomic DNA extracted from peripheral blood. Data analysis was performed using bioinformatics tools. Genetic variants interpretation was based on ACMG.ResultsMSI analysis indicated MSI-H phenotype, and IHC staining proved no expressions of MSH2 and MSH6 proteins. MLPA and NGS data showed no pathogenic variants in MMR genes. Further analysis of NGS data revealed a candidate WRN frameshift variant (p.R389Efs*3), which was validated with Sanger sequencing. The variant was interpreted as pathogenic since it met the criteria based on the ACMG guideline including very strong (PVS1), strong (PS3), and moderate (PM2).ConclusionWRN is a DNA helicase participating in DNA repair pathways to sustain genomic stability. WRN deficient function may contribute to CRC development that is valuable for further investigation as a candidate gene in hereditary cancer syndrome diagnosis.

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

“…The tumor suppressor WRN encodes an enzyme from the RECQ gene family, which is essential for maintaining genomic stability [ 70 ]. Germline variants of WRN were described in HBOC and early-onset familial colorectal cancer [ 71 , 72 , 73 ]. The heterozygous loss at exon 1 of PMS2 was identified among the 17 rare CNVs detected in this patient, as discussed above.…”

Comparative Efficacy of Various Formalin Fixatives for Molecular Diagnosis in Pathological Tissues

“…근래에 조직학적 시료인 포르말린으로 고정된(formalinfixed paraffin-embedded, FFPE) 조직에서의 DNA 추출과 이 를 이용한 다양한 분자병리 검사는 진단뿐만 아니라 더 나아가 차세대 염기서열분석(next generation sequencing, NGS) 검사와 같이 정밀 의료 및 표적 치료를 위한 진단 에도 활용되고 있다 (Norouzi et al, 2021;McDonough et al, 2019;Fujii et al, 2022). 따라서, 조직학적 병리 시료는 단순 한 진단의 목적에서 치료 및 예후, 예측, 표적 치료까지 그 영역 및 활용도를 높이고 있다.…”

“…우에 microsatellite stable (MSS)로 분류하였다 (Sood et al, 2001;Kim and Park, 2006;Bilbao-Sieyro et al, 2014) The pH of each formalin was measured 10 times There was no significant difference in one-way ANOVA (Bramwell et al, 1988;Turashvili et al, 2012). (Lee, 2019;Newton et al, 2020;Norouzi et al, 2021;DiGuardo et al, 2021;Fujii et al, 2022).…”