Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

Porkka, Noora; Olkinuora, Alisa; Kuopio, Teijo; Ahtiainen, Maarit; Eldfors, Samuli; Almusa, Henrikki; Mecklin∥, Jukka–Pekka; Peltomäki, Païvi

doi:10.18632/oncotarget.27538

Cited by 11 publications

(12 citation statements)

References 56 publications

(67 reference statements)

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“…MMRs is a DNA damage repair mechanism. Functional loss of key genes in this mechanism leads to DNA replication errors [ 24 ], higher somatic mutations, and tumorigenesis [ 22 , 25 ]. To evaluate the role of NFE2L2 in tumorigenesis, we analyzed the correlation between NFE2L2 expression and MMR gene mutation levels.…”

Section: Resultsmentioning

confidence: 99%

NFE2L2 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltration in Brain Lower Grade Glioma: A Pan-Cancer Analysis

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nuclear factor, erythroid 2 like 2 (NFE2L2, NRF2) is a transcription factor that regulates various antioxidant enzymes. It plays a vital physiological role in regulating oxidative stress and inflammatory response. However, the roles of NFE2L2 in human cancers are still unclear. Our study is aimed at analyzing the prognostic value of NFE2L2 in pan-cancer and at revealing the relationship between NFE2L2 expression and tumor immunity. The present study revealed that NFE2L2 was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels and DNA methyltransferase expression in human pan-cancer. In particular, pan-cancer survival analysis indicated that NFE2L2 expression was associated with adverse outcomes—overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI)—in adrenocortical carcinoma (ACC), brain lower grade glioma (LGG), and pancreatic adenocarcinoma (PAAD) patients. A positive relationship was also found between NFE2L2 expression and immune infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, especially in breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), LGG, liver hepatocellular carcinoma (LIHC), and prostate adenocarcinoma (PRAD). Additionally, NFE2L2 expression was positively correlated with the immune score and the expression of immune checkpoint markers in LGG. In conclusion, these results indicate that transcription factor NFE2L2 is a potential prognostic biomarker and is correlated with immune infiltration in LGG.

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Section: Resultsmentioning

confidence: 99%

NFE2L2 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltration in Brain Lower Grade Glioma: A Pan-Cancer Analysis

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…However, not all LS CRCs fit the archetype that these guidelines are based on. Multiple studies using IHC, MSI analysis, and/or sequencing have shown that up to 6.9% (54/58; 95% CI: 83.3–98.1%) of CRCs that develop in LS gene carriers are MMR proficient [ 28 , 29 , 30 , 31 ]. Given the variety of assays used and the consistency of these observations, this likely represents the development of sporadic MMR-proficient tumours rather than test insensitivity.…”

Section: Limitations Of Ls Screening Guidancementioning

confidence: 99%

“…MMR deficiency testing of the tumour, by MSI analysis or immunohistochemistry (IHC) to show loss of MMR protein expression, is used to identify potential LS-associated CRCs. The utility of MMR deficiency testing is based on the repeated observation that nearly all LS CRCs are MMR deficient [ 28 , 29 , 30 , 31 ], following somatic loss of function of the second allele of the germline-affected MMR gene according to Knudson’s two-hit hypothesis [ 32 ]. Subsequently, MMR-deficient CRCs are tested for BRAF c.1799T>A (p.V600E) variants and MLH1 promoter methylation to improve screening specificity, as both are associated with sporadic tumours ( p < 0.001) [ 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

Gallon

Gawthorpe

Phelps

et al. 2021

Cancers

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International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.

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“…In the two endometrial MSH2-positive cancers, the remaining MMR proteins were also expressed, although the PCR microsatellite instability analysis results were unstable (data not shown), consistent with results previously reported [ 22 , 23 ]. In the two breast lesions, other carcinogenetic pathways different from the MMR system may be activated [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Cuatrecasas

Gorostiaga

Riera

et al. 2020

Cancers

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The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3′-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3′-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3′-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.

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Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

Cited by 11 publications

References 56 publications

NFE2L2 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltration in Brain Lower Grade Glioma: A Pan-Cancer Analysis

NFE2L2 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltration in Brain Lower Grade Glioma: A Pan-Cancer Analysis

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

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