Tumor infiltrating lymphocytes (TILs) in endometrioid and clear cell ovarian carcinoma: Characterization, association with mismatch repair system deficiency and endometriosis, and prognostic implications.

e17549 Background: In contrast to high-grade serous ovarian cancer, relationship between tumor infiltrating lymphocytes (TILs) with endometrioid (EC) and clear cell ovarian carcinomas (CC) are less known. However, these tumors are thought to arise from a transformed endometriosis, a disease with a marked inflammatory response, and are also more related to Lynch syndrome. The characterization of TILs in these tumors could lead to stratify patients according to their prognosis and to identify candidates for immumotherapy in case of relapse. Methods: We conducted a retrospective observational study of 121 patients with EC and CC, diagnosed and treated in La Paz University Hospital, from November 1992 until December 2013. An expert pathologist reviewed the histopathological diagnosis, using the immunohistochemical algorithm with WT1, p53, Napsin A and progesterone receptor, and the presence of endometriosis. Clinicopathological data, genetic testing and personal and familial background were collected. Tissue-microarrays (TMAs) were used to analyze CD8+, CD4+ and CD3+ intra-epithelial TILs, according to the score designed by the Ovarian Tumor Tissue Analysis Consortium, peritumoral and endometriosis lymphocytes, ARID1A, MLH1, PMS2, MSH2 and MSH6. Software SPSS18 version was used for descriptive and statistical analysis. Results: Mean age was 54.3 years, and the median follow-up 10.02 years. 48.8% were CC and 51.2% EC, of which, 55.9% were well-differentiated, 32.2% moderately and 11.9% poorly. 58.8% of patients were diagnosed in early stages and 41.2% in advanced ones. 9.1% had family history of ovarian, colorectal or endometrial cancer and 16.5% of breast cancer. 37.2% of patients had a relapse (median progression-free survival of 31 months) and 41.6% died (32.6% related to the tumor). 55.4% of the patients had endometriosis (53.2% were EC and 57.6% CC). 8.2% had lost of MLH1, PMS2, MSH2 or MSH6 and 42% lost ARID1A expression. Moderate or high levels of CD3+, CD8+ and CD4+ TILs were seen in the 57.9%, 53.7% and 1.1%, respectively. There was no relationship between TILs and the lost of MLH1, PMS2, MSH2 and MSH6. Moderate or higher levels of CD3+ TILs were related with better overall survival (OS) only in early stages (p = 0.045). Increased CD8+ TILs in EC patients were associated with a trend towards an improved OS in comparison with those patients with lower or negative CD8+ TILs. Moderate o higher levels of CD8+ TILs were also associated, without statistical significance, with the presence of endometriosis and ARID1A. Conclusions: In our study CD3+ TILs correlated to a better OS, but only in early stages of CC and EC. CD8+ TILs were also associated with a tendency to better OS in EC. We did not find statistically significant association between TILs and Mismatch Repair System deficiency, ARID1A or endometriosis.

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Functional Specifics of the MutL Protein of the DNA Mismatch Repair System in Different Organisms

Russian Journal of Bioorganic Chemistry ◽

10.1134/s1068162020060217 ◽

2020 ◽

Vol 46 (6) ◽

pp. 875-890

Author(s):

M. V. Monakhova ◽

M. A. Milakina ◽

R. M. Trikin ◽

T. S. Oretskaya ◽

E. A. Kubareva

Keyword(s):

Mismatch Repair ◽

Dna Mismatch Repair ◽

Repair System ◽

Dna Mismatch ◽

Dna Mismatch Repair System ◽

Mismatch Repair System

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Poorly Repaired Mismatches in Heteroduplex DNA are Hyper-Recombinagenic in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/142.2.407 ◽

1996 ◽

Vol 142 (2) ◽

pp. 407-416 ◽

Cited By ~ 3

Author(s):

P Manivasakam ◽

Susan M Rosenberg ◽

P J Hastings

Keyword(s):

Saccharomyces Cerevisiae ◽

Mismatch Repair ◽

Genetic Markers ◽

Meiotic Recombination ◽

Repair System ◽

Normal Allele ◽

Heteroduplex Dna ◽

Mismatch Repair System ◽

Postmeiotic Segregation ◽

System Operating

Abstract In yeast meiotic recombination, alleles used as genetic markers fall into two classes as regards their fate when incorporated into heteroduplex DNA. Normal alleles are those that form heteroduplexes that are nearly always recognized and corrected by the mismatch repair system operating in meiosis. High PMS (postmeiotic segregation) alleles form heteroduplexes that are inefficiently mismatch repaired. We report that placing any of several high PMS alleles very close to normal alleles causes hyperrecombination between these markers. We propose that this hyperrecombination is caused by the high PMS allele blocking a mismatch repair tract initiated from the normal allele, thus preventing corepair of the two alleles, which would prevent formation of recombinants. The results of three point crosses involving two PMS alleles and a normal allele suggest that high PMS alleles placed between two alleles that are normally corepaired block that corepair.

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Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma

Diagnostic Pathology ◽

10.1186/s13000-021-01071-w ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Huijuan Ge ◽

Yaoxin Xiao ◽

Guangqi Qin ◽

Yanzi Gu ◽

Xu Cai ◽

...

Keyword(s):

Cell Carcinoma ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Tumor Infiltrating Lymphocytes ◽

Tissue Microarrays ◽

Ovarian Clear Cell Carcinoma ◽

Repair Deficiency ◽

Ovarian Epithelial Carcinoma ◽

Histological Characteristics ◽

Infiltrating Lymphocytes

Abstract Background Ovarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). ARID1A mutation is an important pathogenetic mechanism in OCCC that leads to loss of ARID1A expression in approximately half of OCCCs. However, the correlation of MMR status and ARID1A deficiency is unclear. The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency. Methods A cohort of 176 primary OCCC patients was enrolled and review included histological characteristics (nuclear atypia, necrosis, mitosis, stromal hyalinization, and background precursors) and host inflammatory response (tumor-infiltrating lymphocytes, peritumoral lymphocytes, intratumoral stromal inflammation and plasma cell infiltration). Immunohistochemical staining of MLH1, PMS2, MSH2, MSH6 and ARID1A was performed using tissue microarrays. Results dMMR was detected in 10/176 tumors (6 %), followed by MSH2/MSH6 (6/176), MLH1/PMS2 (3/176), and MSH6 (1/176). The average age of patients with dMMR was younger than that of patients with intact MMR (46 y vs. 53 y). Tumors with diffuse intratumoral stromal inflammation remained significantly associated after multivariate analysis. ARID1A expression was absent in 8 patients with dMMR (8/10), which is a significantly higher frequency than that observed in patients with intact MMR (80 % vs. 43.2 %). Conclusions Our study indicates that diffuse intratumoral stromal inflammation of OCCCs is associated with dMMR, with loss of MSH2/MSH6 expression being most frequent. dMMR is strongly associated with the loss of ARID1A expression in OCCC.

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Saturation of DNA Mismatch Repair and Error Catastrophe by a Base Analogue in Escherichia coli

Genetics ◽

10.1093/genetics/161.4.1363 ◽

2002 ◽

Vol 161 (4) ◽

pp. 1363-1371

Author(s):

Kazuo Negishi ◽

David Loakes ◽

Roel M Schaaper

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Repair System ◽

Mutagenic Action ◽

Wild Type ◽

Dna Mismatch ◽

Cell Counts ◽

Error Catastrophe ◽

Mismatch Repair System

Abstract Deoxyribosyl-dihydropyrimido[4,5-c][1,2]oxazin-7-one (dP) is a potent mutagenic deoxycytidine-derived base analogue capable of pairing with both A and G, thereby causing G · C → A · T and A · T → G · C transition mutations. We have found that the Escherichia coli DNA mismatch-repair system can protect cells against this mutagenic action. At a low dose, dP is much more mutagenic in mismatch-repair-defective mutH, mutL, and mutS strains than in a wild-type strain. At higher doses, the difference between the wild-type and the mutator strains becomes small, indicative of saturation of mismatch repair. Introduction of a plasmid containing the E. coli mutL+ gene significantly reduces dP-induced mutagenesis. Together, the results indicate that the mismatch-repair system can remove dP-induced replication errors, but that its capacity to remove dP-containing mismatches can readily be saturated. When cells are cultured at high dP concentration, mutant frequencies reach exceptionally high levels and viable cell counts are reduced. The observations are consistent with a hypothesis in which dP-induced cell killing and growth impairment result from excess mutations (error catastrophe), as previously observed spontaneously in proofreading-deficient mutD (dnaQ) strains.

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Antagonism of Ultraviolet-Light Mutagenesis by the Methyl-Directed Mismatch-Repair System of Escherichia coli

Genetics ◽

10.1093/genetics/154.2.503 ◽

2000 ◽

Vol 154 (2) ◽

pp. 503-512 ◽

Cited By ~ 1

Author(s):

Hongbo Liu ◽

Stephen R Hewitt ◽

John B Hays

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Excision Repair ◽

Spontaneous Mutation ◽

Repair System ◽

Uv Mutagenesis ◽

Repair Protein ◽

Mismatch Repair System

Abstract Previous studies have demonstrated that the Escherichia coli MutHLS mismatch-repair system can process UV-irradiated DNA in vivo and that the human MSH2·MSH6 mismatch-repair protein binds more strongly in vitro to photoproduct/base mismatches than to “matched” photoproducts in DNA. We tested the hypothesis that mismatch repair directed against incorrect bases opposite photoproducts might reduce UV mutagenesis, using two alleles at E. coli lacZ codon 461, which revert, respectively, via CCC → CTC and CTT → CTC transitions. F′ lacZ targets were mated from mut+ donors into mutH, mutL, or mutS recipients, once cells were at substantial densities, to minimize spontaneous mutation prior to irradiation. In umu+ mut+ recipients, a range of UV fluences induced lac+ revertant frequencies of 4–25 × 10−8; these frequencies were consistently 2-fold higher in mutH, mutL, or mutS recipients. Since this effect on mutation frequency was unaltered by an Mfd− defect, it appears not to involve transcription-coupled excision repair. In mut+ umuC122::Tn5 bacteria, UV mutagenesis (at 60 J/m2) was very low, but mutH or mutL or mutS mutations increased reversion of both lacZ alleles roughly 25-fold, to 5–10 × 10−8. Thus, at UV doses too low to induce SOS functions, such as Umu2′D, most incorrect bases opposite occasional photoproducts may be removed by mismatch repair, whereas in heavily irradiated (SOS-induced) cells, mismatch repair may only correct some photoproduct/base mismatches, so UV mutagenesis remains substantial.

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