Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)

Abstract

Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months.

Squamous Cell Carcinoma of the Lung With Microsatellite Instability in a Patient With Lynch Syndrome: A Case Report

“…In the literature, three cases of lung dMMR adenocarcinoma of the lung have been reported in patients with Lynch syndrome, including a Muir-Torr syndrome (a form of Lynch syndrome); but, to the best of our knowledge, no dMMR squamous cell carcinoma of the lung has ever been described. 2 , 3 , 4 The risk of squamous cell carcinoma of the lung in Lynch syndrome is the same as that in the general population, but the MSI status reported above clearly indicates that this cancer is not sporadic but directly linked to Lynch syndrome, and it is even uncertain that smoking played a role in carcinogenesis.…”

Locally advanced undifferentiated small round cell sarcoma of the lung with novel SDCCAG8-AKT3 fusion and type II tumor immunity in the microenvironment: a rare case report

“…Herein, we have firstly reported a PMS2 mutation and a new SDCCAG8-AKT3 (S19:A2) gene fusion in USRCS. The PMS2 gene is located in chromosome 7p22, and PMS2 abnormalities can result in dMMR and MSI-H in endometrial, ovarian, colorectal, and lung cancers (14). Mutation of PMS2 might have contributed to the TMB-H and MSI-H genotype in this young male.…”

Crosstalk among disulfidptosis-related lncRNAs in lung adenocarcinoma reveals a correlation with immune profile and clinical prognosis

“…TME is previously suggested to be associated with LUAD distant metastases, drug sensitivity, and immunotherapeutic response [ [24] , [25] , [26] ]. Stromal and immune cell levels within TME can be represented by stromal score and immune score, respectively.…”