scholarly journals Clinical and genetic aspects of differential diagnostics of hereditary non-polyposis colorectal cancer

2019 ◽  
Vol 6 (2) ◽  
pp. 21-27
Author(s):  
A. V. Semyanikhina ◽  
A. O. Rasulov ◽  
L. N. Lyubchenko
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Heterogeneous Group ◽  
Differential Diagnostics ◽  
Genetic Characteristics ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Long Time

Lynch syndrome was synonymous with hereditary non-polyposis colorectal cancer for a long time, however, mapping of the DNA mismatch repair (MMR) genes has led to distinguish Lynch syndrome as an independent syndromic unit from a number of Lynch-like syndromes that phenotypically mimic with the most frequent hereditary variant of colon cancer but genetically representing quite a heterogeneous group. This article presents up to date clinical and genetic characteristics of Lynch syndrome and Lynch-like conditions.

Variable DNA mismatch repair-associated gene profiles in colorectal versus uterine cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11610-11610
Author(s):  
Tabari Baker ◽  
Safoora Deihimi ◽  
Lainie P. Martin ◽  
Michael J. Hall ◽  
Heather Hampel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Dna Mismatch Repair ◽  
Uterine Cancer ◽  
Study Cohort ◽  
Specific Mutation ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Uterine Cancers

11610 Background: DNA mismatch repair (MMR) plays an important role in maintaining DNA synthesis fidelity in the genome. Mutation in MMR genes occurs in colorectal and uterine cancers and leads to increased mutation burden that is associated with response to immune checkpoint inhibitors. It is unknown if there is an MMR gene-specific mutation signature in MMR-deficient tumors, or whether mutations in MMR genes drive specific mutation patterns. Methods: The study cohort consisted of 1060 uterine cancer (UtCa), and 797 colorectal cancer (CRC) cases consecutively submitted to Caris Life Science for molecular profiling using multiple technologies, including next generation sequencing (NGS), immunohistochemistry (IHC), and in situ hybridization (ISH). Mutation, IHC-positive, and ISH-positive frequencies were compared using Fisher’s exact test (p-value < 0.05 considered significant). Results: In total, 1,857 tumors were examined. Of the 797 CRC cases, 115 (14.4%) had at least one mutation in MLH1, MSH2, or MSH6. Nineteen (19; 2.3%) of the CRC cases had mutations in multiple MMR related genes. Of the 1060 UtCa cases, 52 (4.9%) had at least one mutation in MLH1, MSH2, or MSH6. Twenty-two (22; 2.1%) of the UtCa cases had mutations in multiple MMR related genes. Colorectal cancers that were MLH1, MSH2, and MSH6 mutated enriched for rare, lineage specific co-mutations, including KRAS A146T (4/32 MLH1-mutated cases; 12.5%). Uterine cancers that were MLH1, MSH2, and MSH6 mutated also enriched for several co-mutations, including ARID1A (8/9 MLH1-mutated cases; 88.9%), a SWI-SNF chromatin remodeling complex family member. Further analyses revealed differences in PD-L1 positivity between MMR mutated CRCs versus UtCa (8/131; 6.1% versus 8/51; 15.7%). Tumor mutational load (defined as the total number of non-synonymous mutations per Mb sequenced) was 35 mutations per Mb in CRC and 51 mutations per Mb in UtCa. Conclusions: There are differences in mutation signatures between uterine and colorectal cancer, and possible additional molecular targets for combination with immune checkpoint therapies. Further analysis of MMR gene-specific differences in molecular profiles is ongoing and will be discussed.

scholarly journals Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants

2016 ◽  
Vol 113 (15) ◽  
pp. 4128-4133 ◽  
Author(s):  
Hellen Houlleberghs ◽  
Marleen Dekker ◽  
Hildo Lantermans ◽  
Roos Kleinendorst ◽  
Hendrikus Jan Dubbink ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Embryonic Stem ◽  
Mismatch Repair Gene ◽  
Missense Mutations ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Pathogenic Variants

Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that “oligo targeting” can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR-deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors.

scholarly journals High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 621
Author(s):  
Vania Balderrama Brondani ◽  
Luciana Montenegro ◽  
Amanda Meneses Ferreira Lacombe ◽  
Breno Marchiori Magalhães ◽  
Mirian Yumie Nishi ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Germline Mutation ◽  
Pediatric Patients ◽  
Dna Mismatch Repair ◽  
Malignant Neoplasm ◽  
Adrenocortical Tumors ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Dismal Prognosis

Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for the MMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.

scholarly journals The T/G mutation in exon 8 of HMSH2 gene in the sporadic colon cancer patients

2006 ◽  
Vol 53 (2) ◽  
pp. 57-60
Author(s):  
Eva Langner ◽  
Karolina Przybyzowska ◽  
Galbfach Przemyszaw ◽  
Janusz Kunierz ◽  
Beata Smolarz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Histological Grade ◽  
Clinical Parameters ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Significant Difference ◽  
Hereditary Nonpolyposis ◽  
Sporadic Colon Cancer ◽  
The Relationship

The DNA mismatch repair (MMR) system guards against genomic instability, therefore the mutations in the human MMR genes cause the majority of the hereditary nonpolyposis colorectal cancer (HNPCC) and a small percentage of the sporadic colon cancer. hMSH2 is one of MMR genes involved in the correction of mispairing during replication and its mutations are associated with both - microsatellite instability and the hereditary and sporadic colon tumor genesis. The aim of this study was to analyze the T/G mutation (codon 458) in exon 8 of hMSH2 gene in the sporadic colon cancer cells. We also examined the relationship between the T/G mutation of hMSH2 gene, and the selected prognostic factors such as Dukes? stage, histological grade and lymph node metastasis. We analyzed samples of tumor from 75 patients with sporadic colorectal cancers. The mutation in the hMSH2 gene ware determined by the RFLP-PCR. We found T/G mutation in exon 8 of hMSH2 gene in 5 patients (6,7%). There was no statistically significant difference between this mutation and selected clinical parameters. The results of our studies revealed that mutations of hMSH2 gene may lead to development of colorectal cancer. No dependence between the mutation of hMSH2 gene and clinical parameters, suggests that the mutation of hMSH2 gene may have a critical significance for the first steps of carcinogenesis in colon epithelial.

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