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1.
Int J Clin Oncol ; 24(9): 999-1011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273487

RESUMO

Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSß, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/fisiologia , Neoplasias Encefálicas/genética , Criança , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/genética , Molécula de Adesão da Célula Epitelial/genética , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutação
2.
Gynecol Oncol ; 153(3): 487-495, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922603

RESUMO

OBJECTIVE: Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC. METHODS: ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed. RESULTS: Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis. CONCLUSIONS: ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype.


Assuntos
Carcinoma/classificação , DNA Polimerase II/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/classificação , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Fatores Etários , Índice de Massa Corporal , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/secundário , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida
3.
Int J Cancer ; 145(3): 705-713, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30693488

RESUMO

Early-onset (<50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Adolescente , Adulto , Criança , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estudos Retrospectivos , Adulto Jovem
4.
J Clin Oncol ; 37(6): 461-470, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30608896

RESUMO

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Testes Genéticos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Predisposição Genética para Doença , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Fenótipo , Valor Preditivo dos Testes
5.
J Gastrointest Cancer ; 50(3): 530-536, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29850986

RESUMO

PURPOSE: DNA mismatch repair (MMR) protein abnormalities among 42 Sudanese colorectal cancer (CRC) patients were assessed. METHODS: Sections were stained by immunohistochemical method to assess the abnormalities of MLH1, MSH2, MSH6, and PMS2. RESULTS: Of the 42 included cases, 34 (80.95%) were MMR protein positive for all MMR proteins under assessment, 3 (7.14%) MSH2 inadequate, and 1 (2.38%) MSH6 inadequate. Abnormal MMR protein expression was found in 4 (9.5%) cases. Of these, 2 (50%) were MSH2 and MSH6 negative and 2 (50%) were MLH1 and PMS2 negative. Regarding microsatellite instability (MSI) results, the three cases that were MSH2 inadequate and positive for the rest by immunohistochemistry (IHC) showed stable results with both BAT 25 and 26. The case that was MSH6 inadequate showed stable results with both BAT 25 and 26. The 2 cases with MSH2- and MSH6-negative results were unstable with both BAT 25 and 26. Of the two cases that were MLH1 and PMS2 negative, one case showed non-evaluable results with both BAT 25 and 26 while the other case was unstable with BAT 26 and not evaluable with BAT 25. CONCLUSIONS: The percentage of MMR protein-negative cases in Sudanese CRC patients appears to be relatively low compared to what is generally reported in certain studies in different countries. Furthermore, MLH1 and PMS2 and MSH2 and MSH6 abnormal expression detected by IHC seems to be the most common form of MMR protein abnormalities in Sudanese CRC patients. Concerning the results of IHC, MLH1 and MSH2 seem to be the most inactivated MMR genes in Sudanese CRC patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Reparo de Erro de Pareamento de DNA , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Sudão/epidemiologia , Adulto Jovem
6.
Australas J Dermatol ; 60(2): 126-133, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30506759

RESUMO

BACKGROUND/OBJECTIVES: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico-pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). METHODS: An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist-initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 individuals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. RESULTS: The 882 individuals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two-thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282; 74.5%). MMR-deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281; 66.5%). The highest AUC for discriminating MMR-deficient sebaceous lesions from MMR-proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). CONCLUSION: The best combination of measured clinico-pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR-deficient sebaceous skin lesions.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias das Glândulas Sebáceas/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias das Glândulas Sebáceas/genética , Adulto Jovem
7.
Zhonghua Bing Li Xue Za Zhi ; 47(11): 827-833, 2018 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-30423605

RESUMO

Objective: To investigate the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) in colorectal cancers and to explore the relationship between MMR expression and clinicopathologic features. Methods: Six hundred and fifty-eight colon cancers were collected from January 2016 to January 2017 at Shengjing Hospital of China Medical University. Of the 658 patients there were 409 male and 249 female. The patients were 20 to 92 years old, with average age of (63±5) years old. Expression of MLH1, MSH2, MSH6 and PMS2 protein was detected by immunohistochemical method. Immunohistochemistry for BRAF V600E was performed in colorectal cancers with loss of MLH1 protein expression. Relationship between MMR protein expression and clinicopathologic features was analyzed statistically. Results: Forty-four cases of 658 cases (6.7%) lost at least one MMR protein expression. Expression deficiency rates of MLH1, MSH2, MSH6 and PMS2 were 4.1%(27/658), 2.3%(15/658), 2.4% (16/658), and 4.3% (28/658), respectively. MMR expression deficiency mainly consisted of combined loss of MLH1/PMS2 (61.4%, 27/44) and MSH2/MSH6 (34.1%, 15/44). Two unique mutations were identified including one MSH6-deficient(2.3%, 1/44) and PMS2-deficient(2.3%, 1/44). Seven cases (25.9%, 7/27) had positive BRAF V600E expression, suggesting BRAF gene mutation related sporadic colorectal cancers. No correlation was observed between the expression of MMR and depth of tumor infiltration, lymph node metastasis, vascular tumor emboli, clinical stage or hematogenous metastasis (P>0.05). MMR status was associated with tumor cell differentiation, histological type and tumor location (P<0.01). Tumors with combined MLH1 and PMS2 loss were associated with mucinous differentiation (P=0.049, P=0.013) and located in the right hemi-colon (P=0.006, P=0.002). Combined MSH2 and PMS2 loss was related to gender, while loss of MSH2 protein was observed more frequently in female patients (P=0.048) and loss of PMS2 protein was seen more frequently in male patients (P=0.031). Conclusions: Patients with MMR protein deficiency have a younger onset age and poorly differentiated tumors. Most tumors are located in the right hemi-colon and have mucinous differentiation.


Assuntos
Neoplasias do Colo/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , China , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/metabolismo , Fatores Sexuais , Adulto Jovem
8.
BMC Med Genet ; 19(1): 176, 2018 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-30268105

RESUMO

BACKGROUND: Hereditary cancer screening (HCS) for germline variants in the 3' exons of PMS2, a mismatch repair gene implicated in Lynch syndrome, is technically challenging due to homology with its pseudogene PMS2CL. Sequences of PMS2 and PMS2CL are so similar that next-generation sequencing (NGS) of short fragments-common practice in multigene HCS panels-may identify the presence of a variant but fail to disambiguate whether its origin is the gene or the pseudogene. Molecular approaches utilizing longer DNA fragments, such as long-range PCR (LR-PCR), can definitively localize variants in PMS2, yet applying such testing to all samples can have logistical and economic drawbacks. METHODS: To address these drawbacks, we propose and characterize a reflex workflow for variant discovery in the 3' exons of PMS2. We cataloged the natural variation in PMS2 and PMS2CL in 707 samples and designed hybrid-capture probes to enrich the gene and pseudogene with equal efficiency. For PMS2 exon 11, NGS reads were aligned, filtered using gene-specific variants, and subject to standard diploid variant calling. For PMS2 exons 12-15, the NGS reads were permissively aligned to PMS2, and variant calling was performed with the expectation of observing four alleles (i.e., tetraploid calling). In this reflex workflow, short-read NGS identifies potentially reportable variants that are then subject to disambiguation via LR-PCR-based testing. RESULTS: Applying short-read NGS screening to 299 HCS samples and cell lines demonstrated >99% analytical sensitivity and >99% analytical specificity for single-nucleotide variants (SNVs) and short insertions and deletions (indels), as well as >96% analytical sensitivity and >99% analytical specificity for copy-number variants. Importantly, 92% of samples had resolved genotypes from short-read NGS alone, with the remaining 8% requiring LR-PCR reflex. CONCLUSION: Our reflex workflow mitigates the challenges of screening in PMS2 and serves as a guide for clinical laboratories performing multigene HCS. To facilitate future exploration and testing of PMS2 variants, we share the raw and processed LR-PCR data from commercially available cell lines, as well as variant frequencies from a diverse patient cohort.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Detecção Precoce de Câncer/métodos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase/métodos , Pseudogenes , Alelos , Linhagem Celular Tumoral , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Detecção Precoce de Câncer/instrumentação , Éxons , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase/normas , Sensibilidade e Especificidade
9.
PLoS One ; 13(8): e0201072, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30096142

RESUMO

OBJECTIVES: To (i) show the outcome benefits of enlarged lymph nodes in node-positive colon cancer cases, as it was shown previously in negative node cases; (ii) disprove the stage migration theory and (iii) list the factors affecting lymph node size and yield. METHODS: A retrospective study including 234 node-positive colon cancer cases was scheduled and performed. All recovered lymph nodes (6969) from 234 cases were microscopically examined in regard to (a) lymph node size (b) presence of metastasis (c) extent of intra-nodal metastasis. On the basis of resulting data, a statistical analysis was performed. RESULTS: Metastases occurred in all size categories, though more often in larger lymph nodes. Fifty-one percent of all metastasised nodes were 2 to 6 mm in size. Approximately half of all nodes >10 mm were microscopically free of cancer. Cases with a small lymph node metastasis to lymph node size ratio (MSR) had a better prognosis than others: 85 months (95% CI: 72-97) vs. 67 months (95% CI: 47-88), p <0.001 (mean, overall survival). To differentiate between cases with the same ratio but different absolute lymph nodes sizes, we divided the cases into two groups that differed in their number of moderate to large lymph nodes. The group with more moderate to large lymph nodes showed a clear outcome benefit: 104 months (95% CI: 86-122) vs. 66 months (95% CI: 54-77), p = 0.014 (mean, overall survival). CONCLUSIONS: Metastasised lymph nodes affect all size categories, and large lymph nodes are not always metastasised. The combination of enlarged lymph nodes and a small lymph node metastasis to lymph node size ratio (MSR) is associated with a better prognosis than others. When enlarged lymph nodes were considered as surrogate markers of an effective local immune response due to nodal hyperplasia, the immune system could be seen as the confounder affecting both lymph node size and prognosis. Our results are pointing in this direction and, along with other reasons, are challenging the stage migration theory.


Assuntos
Neoplasias do Colo/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/cirurgia , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Linfonodos/metabolismo , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco
10.
Mol Carcinog ; 57(12): 1723-1734, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30136313

RESUMO

MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Pharmacological treatment indicates that Casein kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity. Moreover, we found that levels of p-MLH1S477 varied during the cell cycle. In summary, we identified that phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR, the new mechanism here described could have an important impact on tumors overactive in CK2.


Assuntos
Caseína Quinase II/metabolismo , Proteína 1 Homóloga a MutL/química , Proteína 1 Homóloga a MutL/metabolismo , Proteínas MutL/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Reparo de Erro de Pareamento de DNA , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Espectrometria de Massas , Endonuclease PMS2 de Reparo de Erro de Pareamento/química , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Modelos Moleculares , Proteínas MutL/química , Fosforilação , Processamento de Proteína Pós-Traducional , Serina/metabolismo , Células Sf9
11.
Croat Med J ; 59(3): 100-107, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29972732

RESUMO

AIM: To analyze the loss of mismatch repair (MMR) system protein expression in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus (BE). METHODS: This study retrospectively analyzed the data from 70 patients with pathohistological diagnosis of BE or esophageal adenocarcinoma (EAC) treated at the Clinical Department of Pathology and Cytology, University Hospital Center Zagreb, from January 2009 to January 2011. Patients were divided into three groups: BE without dysplasia (22 patients), BE with dysplasia (37 patients), and EAC (11 patients). Immunohistochemical expression of MutL homologue 1 (MLH1), MutS homologue 2 (MSH2), postmeiotic segregation increased 2 (PMS2), and MutS homologue 6 (MSH6) of DNA MMR system was measured and compared with tumor protein p53 expression. RESULTS: A total of 81.8% and 81.8% patients with EAC, 32.4% and 35.1% patients with dysplasia, and 50% and 54.5% patients without dysplasia had loss of MLH1 and PMS2 expression, respectively. Patients with EAC and patients with dysplasia did not have loss of MSH2 and MSH6 expression, and 18.2% patients without dysplasia had loss of MSH2 and MSH6 expression. There was a strong positive correlation between MLH1 and PMS2 expression (Spearman ρ 0.97; P<0.001) and between MSH2 and MSH6 expression (Spearman ρ 0.90, P<0.001) in the entire sample and in all BE groups. No significant correlations of MLH1 and PMS2 with p53 expression were found, except in dysplasia group (φ 0.402, P=0.030 for MSH1; φ 0.371, P=0.042 for PMS2). CONCLUSION: Although we demonstrated considerable loss of MLH1 and PMS2 expression in BE-associated carcinoma sequence, due to the retrospective study design and low number of patients we cannot conclude that MLH1 and PMS2 can be used as biomarkers for patient surveillance and therapy-making decisions. Oxford Centre for Evidence-based Medicine level of evidence: 3.


Assuntos
Adenocarcinoma/metabolismo , Esôfago de Barrett/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Instabilidade de Microssatélites , Proteínas de Neoplasias/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Esôfago de Barrett/patologia , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Metaplasia , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Estudos Retrospectivos , Proteína Supressora de Tumor p53/metabolismo
12.
Gynecol Oncol ; 149(3): 570-574, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656794

RESUMO

OBJECTIVE: Universal screening of endometrial cancer (EC) for Lynch syndrome (LS) has been increasingly implemented in the past five to ten years. Most pathologists initiate screening with immunohistochemistry (IHC) for mismatch repair proteins (MMRPs), using either pre-surgical samplings (endometrial biopsy or curettage, EMB/C) or hysterectomy specimens. We report a systematic assessment of the equivalence of IHC for LS screening on EMB/C versus hysterectomy specimens. METHODS: We identified 99 patients diagnosed with endometrioid EC and performed IHC for MMRPs MLH1, MSH2, MSH6, and PMS2 on their diagnostic EMB/C and paired hysterectomy specimen. Each specimen was scored as MMRP-retained or MMRP-deficient. RESULTS: Ninety-one EMB/Cs had carcinoma, while 8 EMB/Cs showed only complex atypical hyperplasia (CAH). Carcinoma was identified in all 99 hysterectomy specimens. Considering all 99 patients tested, concordance of MMRP expression pattern between EMB/C and paired hysterectomy specimen was 100%. Sixty-nine cases retained all four MMRPs, while 30 were MMRP deficient (26 MLH1- and PMS2-deficient, 3 MSH2- and MSH6-deficient, 1 PMS2-deficient). CONCLUSIONS: In screening for LS in EC, IHC for MMRPs can be performed with identical accuracy on either EMB/C or hysterectomy specimens. Routine testing of diagnostic EMB/Cs may lead to earlier detection of MMRP deficiency, with improved patient uptake of genetic counseling and potential for earlier identification of immunotherapy candidates. Furthermore, reliable IHC-based LS screening performed on EMB/C can guide patient management and genetic counseling in patients unable to undergo hysterectomy.


Assuntos
Carcinoma Endometrioide/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Curetagem , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Imuno-Histoquímica , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Adulto Jovem
13.
S Afr J Surg ; 56(1): 25-29, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29638089

RESUMO

BACKGROUND: To determine the mismatch repair (MMR) protein loss in colorectal cancer (CRC) in north Indian patients and its clinicopathological correlation. METHOD: A prospective study on patients with colorectal cancer from a tertiary level hospital conducted between May 2014 and June 2015. MMR protein loss was determined using immunohistochemistry for MLH1, MSH2, PMS2 and MSH6. RESULTS: 52 patients (38 male and 14 females) of CRC, with median age of 52.5 years who underwent resection form the study group. 18 (35%) patients were < 50 years of age. Family history of malignancy was present in 3 (6 %) patients. A total of 15 (29%) patients had loss of MMR protein of which 7 (46%) were < 50 years. Most common MMR loss was combined loss of MSH2 + MSH6 [6 (11.5%)] followed by isolated loss of PMS2 [5 (9.6%)]. MMR protein loss was more frequent in patients with right side colon cancer [12 (42%)] compared to left [3 (13%)] (p = 0.033). MMR protein loss was seen in 11 (34%) out of 32 patients fulfilling the revised Bethesda criteria compared to 4 (20%) out of 20 patients who did not fulfil the criteria (p = 0.352). CONCLUSION: This study demonstrates high frequency of MMR protein loss in colorectal cancer in north Indian patients which was more common in right colon cancer. Many patients having MMR protein loss do not satisfy the revised Bethesda criteria and would have been missed if selective testing was done. Further research and larger studies are required to validate these findings and develop India specific clinical criteria.


Assuntos
Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Adenocarcinoma/etiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
14.
Ann Surg Oncol ; 25(5): 1374-1380, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29532344

RESUMO

BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.


Assuntos
Índice de Massa Corporal , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Reparo de Erro de Pareamento de DNA , Obesidade/imunologia , Microambiente Tumoral/imunologia , Idoso , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Metástase Linfática , Contagem de Linfócitos , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Obesidade/genética , Estudos Prospectivos , Distribuição Aleatória
15.
J Obstet Gynaecol Res ; 44(5): 966-971, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29436070

RESUMO

A 53-year-old obese woman was referred because of sudden onset of dyspnea and chronic vaginal bleeding. In addition to severe anemia, multiple pulmonary emboli were identified. Pelvic imaging showed an irregular-shaped mass in the region of the endocervix extending to the lower uterine segment. After successful anticoagulant therapy, followed by placement of an inferior vena cava filter, transabdominal hysterectomy and bilateral salpingo-oophorectomy were performed. An immunopathological study resulted in the diagnosis of endocervical serous carcinoma. After the identification of a high level of microsatellite instability (MSI), an immunohistochemical analysis of mismatch repair (MMR) proteins showed the isolated loss of PMS2. Germline testing of MMR genes showed no mutations, indicating that the high MSI had occurred as a result of sporadic isolated loss of the PMS2 gene expression.


Assuntos
Cistadenocarcinoma Seroso/diagnóstico , Instabilidade de Microssatélites , Neoplasias do Colo do Útero/diagnóstico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Embolia Pulmonar/diagnóstico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/cirurgia
16.
Gut ; 67(3): 447-455, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29439113

RESUMO

OBJECTIVE: Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics. DESIGN: 54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111). RESULTS: KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome. CONCLUSIONS: We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.


Assuntos
Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Doença de Hodgkin/terapia , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/metabolismo , Simulação por Computador , Ilhas de CpG , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Segunda Neoplasia Primária/metabolismo , Procarbazina/uso terapêutico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Radioterapia , Adulto Jovem
17.
Biochimie ; 146: 87-96, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29175432

RESUMO

MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLα comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLα is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-α bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-α as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLα heterodimer is discussed.


Assuntos
Núcleo Celular/metabolismo , Reparo de Erro de Pareamento de DNA , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Animais , Humanos , Carioferinas/metabolismo , Camundongos , Endonuclease PMS2 de Reparo de Erro de Pareamento/química , Modelos Moleculares , Proteína 1 Homóloga a MutL/química , Conformação Proteica
18.
Fam Cancer ; 17(2): 225-228, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28819720

RESUMO

Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient's age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias do Colo/patologia , Proteína 1 Homóloga a MutL/análise , Proteína 2 Homóloga a MutS/análise , Adenocarcinoma/genética , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/genética , Metilação de DNA , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Fenótipo
19.
Mol Carcinog ; 56(12): 2663-2668, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28767177

RESUMO

MutLα, a heterodimer consisting of MLH1 and PMS2, plays an important role in DNA mismatch repair and has been shown to be additionally involved in several other important cellular mechanisms. Previous work indicated that AKT could modulate PMS2 stability by phosphorylation. Still, the mechanisms of regulation of MutLα remain unclear. The stability of MutLα subunits was investigated by transiently overexpression of wild type and mutant forms of MLH1 and PMS2 using immunoblotting for measuring the protein levels after treatment. We found that treatment with the cell-permeable serine/threonine phosphatase inhibitor, Calyculin, leads to degradation of PMS2 when MLH1 or its C-terminal domain is missing or if amino acids of MLH1 essential for PMS2 interaction are mutated. In addition, we discovered that the C-terminal tail of PMS2 is relevant for this Calyculin-dependent degradation. A direct involvement of AKT, which was previously described to be responsible for PMS2 degradation, could not be detected. The multi-kinase inhibitor Sorafenib, in contrast, was able to avoid the degradation of PMS2 which postulates that cellular phosphorylation is involved in this process. Together, we show that pharmacologically induced phosphorylation by Calyculin can induce the selective proteasome-dependent degradation of PMS2 but not of MLH1 and that the PMS2 degradation could be blocked by Sorafenib treatment. Curiously, the C-terminal Lynch Syndrome-variants MLH1L749P and MLH1Y750X make PMS2 prone to Calyculin induced degradation. Therefore, we conclude that the specific degradation of PMS2 may represent a new mechanism to regulate MutLα.


Assuntos
Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteínas MutL/metabolismo , Transdução de Sinais , Western Blotting , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteínas MutL/genética , Mutação , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Oxazóis/farmacologia , Compostos de Fenilureia/farmacologia , Fosforilação , Proteólise/efeitos dos fármacos , Serina/genética , Serina/metabolismo , Sorafenibe , Treonina/genética , Treonina/metabolismo
20.
PLoS One ; 12(8): e0181615, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28767665

RESUMO

BACKGROUND: We performed a systematic screening of colorectal cancer (CRC) tissues to investigate whether mismatch repair (MMR) status and ERCC1 protein expression could be predictive of clinical outcomes for these patients following the recommendation of The Evaluation of Genomic Applications in Practice of Prevention (EGAPP). METHODS: The expression of four MMR genes and ERCC1 were assessed by immunohistochemistry (IHC) from cancer tissue samples of 2233 consecutive CRC patients. RESULTS: We observed that most CRC patients with a proficient MMR (pMMR) status tended to have simultaneous ERCC1 protein expression (P< 0.001). Stage III CRC patients with deficient MMR (dMMR) had higher prognoses than the same stage patients with pMMR (DFS: 74% vs 65%, P = 0.04; OS: 79% vs 69%, P = 0.04). Here, dMMR is also associated with poorer survival for stage II patients after chemotherapy (DFS: 66% vs 78%, P = 0.04). Stage II and III patients that were shown to express ERCC1 protein had higher DFS and OS than those that were deficient in expression (stage II, DFS: 83% vs 70%, P = 0.006; OS 85% vs 73%, P = 0.02. Stage III, DFS: 67% vs56%, P = 0.03; OS: 71% vs 57%, P = 0.04). CONCLUSIONS: Our results indicate that dMMR appeared to predictive of a survival benefit for stage III CRC patients. We also found the determination of ERCC1 expression to be useful for predicting DFS or OS for stage II and III CRC patients. In addition, the expression of MMR genes and ERCC1 showed a significant relationship.


Assuntos
Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Expressão Gênica , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Neoplasias Colorretais/metabolismo , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Adulto Jovem
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