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Case 14
Published in Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta, Clinical Cases, 2021
Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta
Lynch syndrome (hereditary non-polyposis colorectal cancer)Autosomal dominant disorder caused by mutations in MLH1, MSH2, MSH6 or PMS2 genesExtremely high lifetime risk of colorectal cancer, but also high risk for hepatobiliary, endometrial, ovarian and gastric cancers
Constitutional Mismatch Repair Deficiency Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The MSH6 protein has a highly conserved helix-turn-helix domain associated with an adenine nucleotide and magnesium binding motif (or Walker-A motif) with ATPase activity. MSH6 forms a heterodimer (i.e., MutS α) with MSH2, thus participating in the rectification/repair of single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA.
Common Inherited Genetic Disorders
Published in Attila Lorincz, Nucleic Acid Testing for Human Disease, 2016
A 55-year old female presented to a GI clinic with a past history of polyps developed at age 48 (Figure 15.20). A detailed family history revealed colon and endometrial cancers in several family members. Mutation scanning for MLH1, MSH2, and MSH6 genes was performed. Several variants were detected by DHPLC and further sequencing identified an insertion mutation in the MSH6 gene that was interpreted as disease-causing. Genetic counseling for the patient covered the need for frequent monitoring and her risk for developing CRC and associated cancers. Genetic testing was recommended for other family members to identify those at risk who should be monitored more closely. HNPCC patients like this one usually present with strong family histories of CRC. The point of testing often is to identify the index case and perform pre-symptomatic testing for family members at risk.
Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications
Published in Expert Review of Molecular Diagnostics, 2023
Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera
The DNA mismatch repair (MMR) system consists of four proteins (MLH1, MSH2, MSH6, and PMS2). The MMR protein heterodimers are essential for detecting and correcting DNA replication errors [36]. When the expression of one or more MMR proteins is absent, this leads to deficient MMR (dMMR). IHC is used to ascertain the presence or absence of nuclear expression for one or more MMR proteins [37]. The lack of nuclear expression in one or more MMR proteins strongly correlates with DNA-based microsatellite instability (MSI) testing. A multicenter, single cohort clinical trial including 149 patients with dMMR/MSI-H tumors treated by pembrolizumab reported objective responses in 39.6% of patients, with 78% of responders experiencing a response duration of 6 months, and OS was consistent across various tumor types. These results established dMMR/MSI-H as the first non-cancer-specific biomarker. Hagi et al. conducted a retrospective cohort study including 200 patients with unresectable or recurrent GC and prior or scheduled treatment with nivolumab as third-line or higher therapy [24]. The study demonstrated that dMMR was associated with a greater response probability and longer PFS duration (HR = 2.35, 95% CI: 1.48–3.75, P < 0.001). The authors concluded that dMMR may be a valuable biomarker for nivolumab treatment efficacy in GC.
Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies
Published in Expert Opinion on Investigational Drugs, 2022
Javier Ros, Nadia Saoudi, Francesc Salvà, Iosune Baraibar, Guzman Alonso, Josep Tabernero, Elena Elez
Patients with mCRC presenting MSI status are characterized by the biallelic inactivation of DNA MMR genes caused by germline mutations, somatic mutations, or epigenetic silencing. DNA mismatch machinery consists of four proteins (MSH2, MSH6, MLH1, and PMS2) that form heterodimers (MLH1/PMS2 and MSH2/MSH6) to correct base-pair errors that arise during DNA synthesis in proficient MMR cells. When these proteins misfunction, an accumulation of error correction causes insertions and deletions to accumulate and mutation frequency to increase, ultimately leading to cancer. Germline mutations in dMMR genes or the epithelial cell adhesion molecule (EPCAM, leading to epigenetic silencing of MSH2) are the hallmarks of Lynch syndrome, which accounts for approximately 3% of CRC. Affected patients are at risk of presenting endometrial and colorectal tumors, along with other cancers [85,86]. On the other hand, both epigenetic silencing of the MLH1 gene promoter gene and the BRAF-V600E mutation are associated with sporadic CRC, as somatic BRAF-V600E mutations increase BRAF/MEK/ERK signaling, resulting in the CpG island methylator phenotype and MLH1 silencing through the transcriptional repressor MAFG [87], ultimately leading to dMMR. MSI status has prognostic and predictive value and should be determined in every patient with CRC. Both IHC and genome sequence tools using PCR are accepted testing techniques to confirm MSI and MMR status [64]. Furthermore, MSI status can be detected in either tumor tissue or blood. Concordance between techniques is high (>90%) [88].
Immune checkpoint inhibitors for recurrent endometrial cancer
Published in Expert Review of Anticancer Therapy, 2022
Levent Mutlu, Justin Harold, Joan Tymon-Rosario, Alessandro D. Santin
Nivolumab is a fully human anti-PD-1 monoclonal antibody. The clinical efficacy of nivolumab in two patients with recurrent widespread metastatic endometrial carcinoma was initially reported in 2016. Both patients had recurrent, widespread disease with carcinomatosis; WES revealed a hotspot POLE mutation and MSH6 germline mutation (i.e. Lynch Syndrome) with mutational burdens of 117 mut/Mb and 33.5/Mb, respectively. PD-L1 staining showed 20% and 5% positivity. After treatment with nivolumab 3 mg/kg every 2 weeks, both patients demonstrated a dramatic reduction of disease burden based on RECIST criteria[37]. The efficacy of nivolumab was subsequently studied in a phase II trial administering nivolumab at a dose of 240 mg every 2 weeks. Patients with soft tissue sarcoma, cervical cancer, and endometrial cancer were enrolled, with 22 patients in the endometrial cancer cohort. The overall ORR was 23%. MSI testing was done in 8 patients with endometrial cancer, and 2 MSI-H patients had complete (100%) response, as opposed to zero of 6 patients with MSS endometrial cancer [38]. Additionally, 25% of the patients with PD-L1 > 1%, 21% of the patients with PD-L1 < 1% had objective response rates; further supporting the importance of the MSI status for treatment response. In an NCI-MATCH trial [39], nivolumab was tested in MMR deficient noncolorectal cancers. The cohort included 13 patients with endometrial cancer. The ORR was 45% (6/13 patients) and 15% (2/13 patients) had a complete response. Nivolumab was well tolerated, and the most common side effects were fatigue (40%), anemia (33%) and rash (17%).