Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population

Kagawa, Makoto; Kawakami, Satoru; Yamamoto, Azusa; Suzuki, Okihide; Kamae, Nao; Eguchi, Hidetaka; Okazaki, Yasushi; Yamamoto, Gou; Akagi, Kiwamu; Tamaru, Jun‐ichi; Yamaguchi, Tatsuro; Arai, Tomio; Ishida, Hideyuki

doi:10.1007/s10147-021-01922-y

Cited by 4 publications

(1 citation statement)

References 46 publications

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“…Routine inclusion of MMR protein detection in tumor IHC staining can provide important clues for Lynch screening. An upper uroepithelial carcinoma with an MSH2 germline variant is the most frequent, while bladder cancer is relatively rare, among Lynch-associated uroepithelial tumors ( 13 , 14 ). Skeldon et al.…”

Section: Discussionmentioning

confidence: 99%

Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome

Cheng

Liu

et al. 2022

Front. Oncol.

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BackgroundLynch syndrome is a genetic disease characterized by abnormal DNA replication caused by germline variation in the mismatch repair (MMR) gene. There are rare non-classical phenotypes with loss of MMR protein expression and inconsistent microsatellite stability (MSS) in Lynch syndrome-related colorectal cancers. However, the difference between microsatellite instability (MSI) of extraintestinal tumors in a patient with Lynch syndrome has been closely studied. Herein, we reported the non-classical phenotypes of mismatch repair deficiency (dMMR) and MSI in four cases of Lynch syndrome in patients with colorectal cancer and other primary and metastatic tumors.MethodsA retrospective analysis was conducted on four patients diagnosed with Lynch syndrome between 2018 and 2022 in the Department of Pathology of the Rocket Forces Specialized Medical Center. A one-step immunohistochemical (IHC) assay was employed to detect loss in the expression of Lynch syndrome-associated MMR proteins (MLH1, PMS2, MSH2, and MSH6). MSI detection was performed in both primary and metastatic tumors at different sites in the four patients using NCI 2B3D (BAT25, BAT26, D2S123, D17S250, and D5S346) and single nucleotide site (BAT25, BAT26, NR21, NR24, NR27, and MONO27) methods. In addition, related MMR gene germline variation, somatic mutations, and MLH1 gene promoter methylation were analyzed using next-generation sequencing and TaqMan probe-based methylation-specific polymerase chain reaction (MethyLight).ResultsTwo of the four patients were heterozygous for MSH6 germline pathogenic variation, and the other two were heterozygous for MSH2 germline pathogenic variation. In all cases, IHC detection of protein expression of the MMR gene with germline variation was negative in all primary and metastatic tumors; non-classical phenotypes of dMMR and MSI were present between primary and metastatic tumors at different sites. dMMR in Lynch colorectal cancer demonstrated high MSI, whereas MSI in primary and metastatic tumors outside the intestine mostly exhibited MSS or low MSI.ConclusionsThe non-classical dMMR and MSI phenotype are mostly observed in Lynch syndrome, even in the context of MMR protein expression loss. Extraintestinal tumors infrequently present with a high degree of MSI and often exhibit a stable or low degree of MSI.

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Section: Discussionmentioning

confidence: 99%

Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome

Cheng

Liu

et al. 2022

Front. Oncol.

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Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome

Ito,

Yamaguchi,

Kumamoto

et al. 2024

Int J Clin Oncol

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Background Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. Methods We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. Results In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1). Conclusions Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

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Recurrent Papillary Bladder Tumors in a Boy With Lynch Syndrome

Tua-Caraccia¹,

Livingston

Routh

2023

Urology

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Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population

Cited by 4 publications

References 46 publications

Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome

Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome

Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome

Recurrent Papillary Bladder Tumors in a Boy With Lynch Syndrome

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