Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Yokoyama, Tomihisa; Takehara, Kazuhiro; Sugimoto, Nao; Kaneko, Keika; Fujimoto, Etsuko; Okazawa-Sakai, Mika; Okame, Shinichi; Shiroyama, Yuko; Yokoyama, Takashi; Teramoto, Norihiro; Ohsumi, Shozo; Imai, Kazuho; Sugano, Kokichi

doi:10.1186/s12885-018-4489-0

Cited by 34 publications

(26 citation statements)

References 17 publications

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“…of MSI. Indeed, somatic biallelic methylation of the MLH1 promoter is an essential mechanism of gene inactivation in MSI-positive colorectal cancer and endometrial cancer (9,10). MLH1 methylation occurs in approximately 19% of sporadic and approximately 16% of Lynch syndrome colorectal cancers (11).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

Germano

Amirouchene-Angelozzi

Rospo

et al. 2018

Cancer Discovery

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The mismatch repair (MMR) system which detects and corrects base mismatches and insertions and deletions that occur during DNA synthesis is deregulated in approximately 20% of human cancers. MMR-defi cient tumors have peculiar properties, including earlyonset metastatic potential but generally favorable prognosis, and remarkable response to immune therapy. The functional basis of these atypical clinical features has recently started to be elucidated. Here, we discuss how the biological and clinical features of MMR-defi cient tumors might be traced back to their ability to continuously produce new somatic mutations, leading to increased levels of neoantigens, which in turn stimulate immune surveillance. Signifi cance: Tumors carrying defects in DNA MMR accumulate high levels of mutations, a feature linked to rapid tumor progression and acquisition of drug resistance but also favorable prognosis and response to immune-checkpoint blockade. We discuss how the genomic landscape of MMR-defi cient tumors affects their biological and clinical behaviors.

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Section: Introductionmentioning

confidence: 99%

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

Germano

Amirouchene-Angelozzi

Rospo

et al. 2018

Cancer Discovery

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“…Since the loss of MMR protein expression can occur by methylation and mutations in the promoter region, in addition to loss-of-function mutations in the coding region, a validation of the exon sequence would not be su cient to evaluate the MMR expression and function [47][48][49]. Actually, in the present study, only 3 of 9 MMR-D cases presented pathogenic mutations in MLH1, MSH6, or PMS2.…”

Section: Discussionmentioning

confidence: 69%

Next-Generation Sequencing Analysis of Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

Akahane

Kitazono

Yanazume

et al. 2020

Preprint

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Background: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. Methods: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. Results: A total of 49 FFPE and LBC specimens (n=24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. Conclusion: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.

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“…Since the loss of MMR protein expression can occur by methylation and mutations in the promoter region, in addition to loss-of-function mutations in the coding region, a validation of the exon sequence would not be sufficient to evaluate the MMR expression and function [41][42][43]. Actually, in the present study, only 3 of 9 MMR-D cases exhibited pathogenic mutations in MLH1, MSH6, or PMS2.…”

Section: Calculation Of Tmb and Msi Scoresmentioning

confidence: 70%

Analysis by Next-Generation Sequencing Panel Covered 60 Genes and 17 Microsatellite Foci in Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

Akahane¹,

Kitazono²,

Yanazume³

et al. 2020

Preprint

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BackgroundLiquid-based cytology (LBC) is now a widely used method for cytologic screening and diagnosis of cancers. Since the cells are fixed with alcohol-based fixatives and the specimens are stored in a liquid condition, LBC specimens are also conducive for genetic analysis. MethodsHere, we established a small cancer gene panel including 60 genes and 17 microsatellite markers for next-generation sequencing and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. ResultsA total of 53 FFPE and LBC specimens (n=24) were analyzed, revealing characteristic mutations for endometrial cancer including those of PTEN, CTNNB1, PIK3CA, and PIK3R1 . Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, demonstrated almost the same mutations, TMB, and MSI profiles in all cases. ConclusionThese findings demonstrate that the small cancer gene panel proved to be able to detect therapeutically actionable gene mutations in endometrial LBC and FFPE specimens and that LBC specimens obtained by endometrial cancer screening is an alternative and useful source of molecular testing. BackgroundEndometrial cancer is the most common gynecologic cancer worldwide, affecting over 500,000women every year [1]. Since lifestyle changes can affect the risk of developing endometrial cancer, an epidemiological approach is essential to manage the disease [2]. Moreover, genome-wide association studies have identified new susceptibility loci for endometrial cancer in the human genome, providing candidate genes for further studies that aim to unravel the mechanisms driving 4 carcinogenesis, which could offer new opportunities for early screening and detection or identification of therapeutic targets [3]. Unlike squamous cell carcinoma of the uterine cervix with pathogenesis closely related to that of human papilloma virus infection [4], endometrial carcinogenesis is linked to common cancer gene mutations and genome instability [5,6].Cytology specimens including conventional smear, cytospin, liquid-based cytology (LBC), and cell block are valuable sources of routine molecular diagnostics [7]. In fact, extensive studies have been reported that variety of cytology materials, containing LBC specimens, are available for molecular testing by next-generation sequencing (NSG), especially in non-small cell lung cancer [7][8][9][10][11][12].Meanwhile, the endometrial cytology is not only safe and easy clinical procedure but also comparable to suction endometrial biopsy for detecting atypical endometrial hyperplasia and cancers [13][14][15][16].Since 1987 in Japan, a cytologic examination for endometrial cancer screening is established by a national health insurance low. Thereafter, endometrial cytology using a specific device is introduced as a less invasive and less...

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Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Cited by 34 publications

References 17 publications

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

Next-Generation Sequencing Analysis of Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

Analysis by Next-Generation Sequencing Panel Covered 60 Genes and 17 Microsatellite Foci in Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

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