Characterization of a germline splice site variant MLH1 c.678-3T & gt;A in a Lynch syndrome family
In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant,MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient ’s tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, theMLH1 c.678-3T>A variant is considered pathogenic.
Authors: Gordhandas S, Kahn RM, Gamble C, Talukdar N, Maddy B, Nelson BB, Askin G, Christos PJ, Holcomb K, Caputo TA, Chapman-Davis E, Frey MK Abstract The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databas...
This study demonstrates that the IHC approach for both MMR deficiency and V600E BRAF mutation detections is the most efficient approach for Lynch syndrome screening in the Italian population.
ConclusionBRCA andBRCA ‐like variants in CRC patients with LS showed moderate penetrance.BRCA/BRCA ‐like variant carriers had a higher risk for extra ‐colorectal cancers. Surveillance of susceptible organs other than the intestine should be performed for probands and affected family members.
CONCLUSIONS: FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer. PMID: 32540851 [PubMed - as supplied by publisher]
Lynch syndrome (LS) is an autosomal dominant disease caused by a germline mutation in DNA mismatch repair genes which increases the risk of several cancers such as endometrial and colorectal cancers. However, there are only a few reports of peritoneal malignancies in patients with LS. Herein, we report the first case of a primary peritoneal low-grade serous carcinoma in a woman with LS and provide a literature review of peritoneal malignancies in patients with LS. The patient was a 72-yr-old gravid 2 para 2 Japanese woman with a germline mutation in MLH1. She had a history of colon cancer and endometrial cancer and was tre...
ConclusionThese results provide new insights into the molecular mechanisms underlying the pathogenicity ofMLH1 mutations and reaffirm the importance of genetic screening for the early diagnosis of LS.
Colorectal cancer (CRC) is the third most common cancer in the U.S. Most CRC is sporadic, but Lynch Syndrome (LS) is the most common hereditary cancer syndrome predisposing to CRC and involves mismatch repair (MMR) deficiency. LS is secondary to germline mutations in one of four MMR genes (MLH1, MSH2, MSH6, and PMS2). Genetically engineered mouse models carrying germline mutations in MMR genes have significantly contributed to current understanding, but do not recapitulate the disease phenotype in LS patients and tissue-specific mouse models only do so partially.
In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 health...
Conclusion: This cohort demonstrates the effectiveness of LS surveillance and suggests possible tailored surveillance strategies by gene mutation and family history. PMID: 32448028 [PubMed - as supplied by publisher]
ConclusionThese results indicate that there is scope to further increase provision of advice at FCCs to ensure that all carriers receive recommendations about evidence-based risk management. A multi-pronged behaviour change and implementation science approach tailored to specific barriers is likely to be needed to achieve optimal clinician behaviours and outcomes for carriers.