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1.
Zhonghua Bing Li Xue Za Zhi ; 53(7): 702-708, 2024 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-38955702

RESUMO

Objective: To investigate the clinicopathological characteristics and prognostic factors of sporadic mismatch repair deficient (dMMR) colorectal cancer. Methods: A total of 120 cases of sporadic dMMR colorectal cancer from July 2015 to April 2021 were retrospectively collected in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients with Lynch syndrome; synchronous multiple colorectal cancers; preoperative anti-tumor treatments such as chemotherapy and radiotherapy; and those with incomplete follow-up information were excluded based on family history and next-generation sequencing (NGS) test results. Immunohistochemical stains were used to detect the expression of mismatch repair proteins, methylation-specific PCR for methylation testing, and fluorescent PCR for BRAF V600E gene mutation detection. The clinical and pathological data, and gene mutation status were analyzed. Follow-up was done to assess survival and prognosis including progression-free survival and overall survival rate. Results: Sporadic dMMR colorectal cancer occurred more frequently in the right side of the colon, in females, and in the elderly. Morphologically, it was mostly moderately-differentiated, and most patients had low-grade tumor budding. In terms of immunohistochemical expression, MLH1 and PMS2 loss were dominant, and there were age and location-specificities in protein expression. MLH1 methylation was commonly detected in elderly female patients and rare in young male patients; while MLH1 and PMS2 deficiency, and BRAF V600E mutation occurred more often on the right side (P<0.05). The 3-year and 5-year progression-free survival rates were 90.7% and 88.7% respectively, and the 3-year and 5-year overall survival rates were 92.8% and 90.7% respectively. Tumor budding status was an independent risk factor affecting patient recurrence (hazard ratio=3.375, 95% confidence interval: 1.060-10.741, P=0.039), patients with low-grade tumor budding had better prognosis, and those with medium or high-grade tumor budding had poor prognosis. Conclusion: For dMMR colorectal cancer patients, tumor budding status is an independent risk factor for recurrence.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Masculino , Feminino , Prognóstico , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Mutação , Taxa de Sobrevida , Pessoa de Meia-Idade , Idoso , Metilação de DNA , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo
2.
Arq Bras Cir Dig ; 37: e1812, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38958348

RESUMO

The present manuscript aimed to review the historical development and most important contributions regarding Lynch Syndrome since its first description, more than a century ago. In 1895, a reputed pathologist from Michigan University, Dr. Aldred Scott Warthin, got intrigued by the family history of a local seamstress called Pauline Gross. According to her prevision, she would present an early death due to cancer, which actually happened (from the uterus). Historically, her family was designated "Family G", comprising a group recognized as the longest and most detailed cancer genealogy that has ever been studied. Warthin concluded that its members had genetic susceptibility for cancer, and they are, nowadays, considered the first reported Lynch Syndrome family. At that time, however, the medical cancer community was far less receptive to the association between heredity and cancer, despite the description of other families with similar heredograms. Unfortunately, this historical fact remained somewhat dormant until another investigator inaugurated a new era in the understanding of family cancer clusters. After reports and studies from this family and many others, the condition initially called Cancer Family Syndrome was changed to the eponym Lynch Syndrome. This was a recognition of the extensive and dedicated work developed by Dr. Henry Lynch in describing various characteristics of the disease, and his efforts to establish the correct recommendations for its diagnosis and treatment. Although the future announces there is still far to go for a complete understanding of Lynch Syndrome, the remarkable contributions of Pauline's intuition, Warthin's perseverance, and Lynch's work consistency must never be forgotten by those who already have or will still benefit from this knowledge.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , História do Século XX , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/história , História do Século XIX , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/história
3.
Ann Med ; 56(1): 2370568, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38920120

RESUMO

OBJECTIVE: Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women. METHODS: Pre-menopausal women with LS (n = 43) and an age-matched control group of healthy women (n = 128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values. RESULTS: Women with LS were less likely to use CHCs compared to the control group (p = 0.03) and had a more negative perception of CHCs' impact on colorectal cancer (p = 0.023) and endometrial cancer (p = 0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p > 0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p = 0.89) and endometrial cancer (p = 0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p = 0.039). CONCLUSION: This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health.


This study illuminates divergent perceptions of combined hormonal contraceptives and their oncological implications between women with Lynch syndrome and healthy women.Tailored counseling and supportive strategies are essential for empowering women with Lynch syndrome to make informed decisions regarding their gynecologic health.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Feminino , Neoplasias Colorretais Hereditárias sem Polipose/psicologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Adulto , Estudos Transversais , Estudos Prospectivos , Pessoa de Meia-Idade , Inquéritos e Questionários , Neoplasias do Endométrio/psicologia , Medição de Risco , Anticoncepcionais Orais Combinados/efeitos adversos , Estudos de Casos e Controles , Percepção , Anticoncepcionais Orais Hormonais/efeitos adversos
4.
Am Soc Clin Oncol Educ Book ; 44(3): e433576, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38913968

RESUMO

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias Colorretais Hereditárias sem Polipose , Predisposição Genética para Doença , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle , Mutação em Linhagem Germinativa
6.
JCO Clin Cancer Inform ; 8: e2300157, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38838280

RESUMO

PURPOSE: Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. METHODS: Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. RESULTS: Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. CONCLUSION: It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Testes Genéticos , Melhoria de Qualidade , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Testes Genéticos/métodos , Adulto , Registros Eletrônicos de Saúde , Idoso , Predisposição Genética para Doença , California/epidemiologia
7.
Pathologie (Heidelb) ; 45(4): 290-299, 2024 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-38864870

RESUMO

Patients with Lynch syndrome, one of the most common hereditary tumor predisposition syndromes, harbor an increased risk for a broad spectrum of especially gastrointestinal and gynecological tumors. Causative for the syndrome are variants in DNA mismatch repair genes, which are passed on to the offspring at a 50% chance (autosomal dominant inheritance). The tumor tissue of these patients usually shows microsatellite instability, which is of increasing relevance regarding prognosis and therapeutic decisions. The detection of a causative genetic variant in a patient enables predictive testing of family members to provide relief to noncarriers and provide carriers with intensified risk-adapted surveillance. In addition, chemoprevention with aspirin (acetylsalicylic acid) has been proven useful for chemoprevention in studies. Therefore, the diagnosis of Lynch syndrome is important for patients and their relatives.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Feminino , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Aspirina/uso terapêutico , Predisposição Genética para Doença
8.
PLoS One ; 19(6): e0304141, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843250

RESUMO

Lynch syndrome is caused by inactivating variants in DNA mismatch repair genes, namely MLH1, MSH2, MSH6 and PMS2. We have investigated five MLH1 and one MSH2 variants that we have identified in Turkish and Tunisian colorectal cancer patients. These variants comprised two small deletions causing frameshifts resulting in premature stops which could be classified pathogenic (MLH1 p.(His727Profs*57) and MSH2 p.(Thr788Asnfs*11)), but also two missense variants (MLH1 p.(Asn338Ser) and p.(Gly181Ser)) and two small, in-frame deletion variants (p.(Val647-Leu650del) and p.(Lys678_Cys680del)). For such small coding genetic variants, it is unclear if they are inactivating or not. We here provide clinical description of the variant carriers and their families, and we performed biochemical laboratory testing on the variant proteins to test if their stability or their MMR activity are compromised. Subsequently, we compared the results to in-silico predictions on structure and conservation. We demonstrate that neither missense alteration affected function, while both deletion variants caused a dramatic instability of the MLH1 protein, resulting in MMR deficiency. These results were consistent with the structural analyses that were performed. The study shows that knowledge of protein function may provide molecular explanations of results obtained with functional biochemical testing and can thereby, in conjunction with clinical information, elevate the evidential value and facilitate clinical management in affected families.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Proteína 1 Homóloga a MutL , Neoplasias Colorretais Hereditárias sem Polipose/genética , Humanos , Masculino , Proteína 1 Homóloga a MutL/genética , Feminino , Reparo de Erro de Pareamento de DNA/genética , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Adulto , Tunísia , Linhagem , Turquia , Idoso , Mutação de Sentido Incorreto
9.
Eur J Hum Genet ; 32(7): 871-875, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38778081

RESUMO

Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer.


Assuntos
Mutação em Linhagem Germinativa , Humanos , Masculino , Feminino , Linhagem , Pessoa de Meia-Idade , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação com Perda de Função , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia
11.
Genes Chromosomes Cancer ; 63(5): e23237, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38722212

RESUMO

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Proteínas de Ligação a DNA , Genótipo , Fenótipo , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Masculino , Proteínas de Ligação a DNA/genética , Pessoa de Meia-Idade , Adulto , Mutação em Linhagem Germinativa , Idoso , Predisposição Genética para Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia
12.
Int J Clin Oncol ; 29(7): 953-963, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38615286

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Feminino , Masculino , Incidência , Pessoa de Meia-Idade , Idoso , Adulto , Proteína 1 Homóloga a MutL/genética , Metilação de DNA , Sequenciamento do Exoma
14.
Int J Clin Oncol ; 29(7): 944-952, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38642190

RESUMO

BACKGROUND: Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes. METHODS: In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome. RESULTS: UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS. CONCLUSIONS: Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Proteína 1 Homóloga a MutL/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Testes Genéticos
15.
ACS Biomater Sci Eng ; 10(5): 3136-3147, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38663028

RESUMO

Treatment with immune checkpoint inhibitors (ICIs) has shown efficacy in some patients with Lynch syndrome-associated colon cancer, but some patients still do not benefit from it. In this study, we adopted a combination strategy of tumor vaccines and ICIs to maximize the benefits of immunotherapy. Here, we obtained tumor-antigen-containing cell lysate (TCL) by lysing MC38Mlh1 KD cells and prepared liposome nanoparticles (Lipo-PEG) with a typical spherical morphology by thin-film hydration. Anti-PD-L1 was coupled to the liposome surface by the amidation reaction. As observed, anti-PD-L1/TCL@Lipo-PEG was not significantly toxic to mouse intestinal epithelial cells (MODE-K) in the safe concentration range and did not cause hemolysis of mouse red blood cells. In addition, anti-PD-L1/TCL@Lipo-PEG reduced immune escape from colon cancer cells (MC38Mlh1 KD) by the anti-PD-L1 antibody, restored the killing function of CD8+ T cells, and targeted more tumor antigens to bone marrow-derived dendritic cells (BMDCs), which also expressed PD-L1, to stimulate BMDC antigen presentation. In syngeneic transplanted Lynch syndrome-associated colon cancer mice, the combination of anti-PD-L1 and TCL provided better cancer suppression than monoimmunotherapy, and the cancer suppression effect of anti-PD-L1/TCL@Lipo-PEG treatment was even better than that of the free drug. Meanwhile anti-PD-L1/TCL@Lipo-PEG enhanced the immunosuppressive tumor microenvironment. In vivo fluorescence imaging and H&E staining showed that the nanomedicine was mainly retained in the tumor site and had no significant toxic side effects on other major organs. The anti-PD-L1/TCL@Lipo-PEG prepared in this study has high efficacy and good biosafety in alleviating the progression of Lynch syndrome-associated colon cancer, and it is expected to be a therapeutic candidate for Lynch syndrome-associated colon cancer.


Assuntos
Antígeno B7-H1 , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Lipossomos , Animais , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Camundongos , Antígeno B7-H1/metabolismo , Nanomedicina , Linhagem Celular Tumoral , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/imunologia , Humanos , Camundongos Endogâmicos C57BL , Feminino , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Progressão da Doença , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígenos de Neoplasias/imunologia
16.
Semin Oncol Nurs ; 40(3): 151624, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38575458

RESUMO

OBJECTIVES: There is limited evidence on health promotion interventions in people with hereditary cancer syndromes or on their main sources of support and information. This study aimed to understand these patients' experiences and needs, including their information needs, their views on prevention and mental health, and the support they want from nurses. METHODS: This qualitative study included 22 people (8 previvors and 14 survivors) with hereditary breast and ovarian syndrome or Lynch syndrome from 10 European countries. Participants underwent individual semi-structured interviews, which were recorded and transcribed for reflexive thematic analysis. The patient and public involvement panel provided input on study design and thematic analysis. RESULTS: Patient experiences were similar regardless of the country and access to testing and screening. Participants reported receiving little information on the importance of health behaviors for cancer risk and expressed their wish to be followed by cancer professionals. They felt compelled to seek support and information from the internet and patient groups. The main themes identified were: (unmet) informational and support needs, seeing life in a different way, and limitations of health care providers. CONCLUSIONS: People with hereditary cancer syndromes need professionals to be involved in their long-term management and to provide reliable information. As genomics are increasingly integrated in oncology, the need for professionals to support these populations will increase. IMPLICATIONS FOR NURSING PRACTICE: Nurses are crucial for promoting self-management and advocating for patient decision-making; however, they need skills and knowledge to do so. There is a need for nurses to get more involved in understanding hereditary cancer syndromes and an opportunity to take the lead in the care of these people.


Assuntos
Pesquisa Qualitativa , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Idoso , Europa (Continente) , Síndromes Neoplásicas Hereditárias/psicologia , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/psicologia
17.
Front Public Health ; 12: 1369201, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38638480

RESUMO

Introduction: Lynch syndrome patients have an inherited predisposition to cancer due to a deficiency in DNA mismatch repair (MMR) genes which could lead to a higher risk of developing cancer if exposed to ionizing radiation. This pilot study aims to reveal the association between MMR deficiency and radiosensitivity at both a CT relevant low dose (20 mGy) and a therapeutic higher dose (2 Gy). Methods: Human colorectal cancer cell lines with (dMMR) or without MMR deficiency (pMMR) were analyzed before and after exposure to radiation using cellular and cytogenetic analyses i.e., clonogenic assay to determine cell reproductive death; sister chromatid exchange (SCE) assay to detect the exchange of DNA between sister chromatids; γH2AX assay to analyze DNA damage repair; and apoptosis analysis to compare cell death response. The advantages and limitations of these assays were assessed in vitro, and their applicability and feasibility investigated for their potential to be used for further studies using clinical samples. Results: Results from the clonogenic assay indicated that the pMMR cell line (HT29) was significantly more radio-resistant than the dMMR cell lines (HCT116, SW48, and LoVo) after 2 Gy X-irradiation. Both cell type and radiation dose had a significant effect on the yield of SCEs/chromosome. When the yield of SCEs/chromosome for the irradiated samples (2 Gy) was normalized against the controls, no significant difference was observed between the cell lines. For the γH2AX assay, 0, 20 mGy and 2 Gy were examined at post-exposure time points of 30 min (min), 4 and 24 h (h). Statistical analysis revealed that HT29 was only significantly more radio-resistant than the MLH1-deficient cells lines, but not the MSH2-deficient cell line. Apoptosis analysis (4 Gy) revealed that HT29 was significantly more radio-resistant than HCT116 albeit with very few apoptotic cells observed. Discussion: Overall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.


Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Projetos Piloto , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Linhagem Celular , Tolerância a Radiação
18.
Prostate ; 84(10): 945-953, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38629217

RESUMO

BACKGROUND: Pathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA testing from the age of 40. Prospective studies of the outcome of long-term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold >3.0 ng/mL) to evaluate whether our recommendations should be continued. METHODS: This is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI-analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway. RESULTS: Twenty-two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) MSH2 carriers and 8/61 (13.1%) MSH6 carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI-high. SIR was 9.54 (95% CI 5.98-14.45) for all MMR genes, 13.0 (95% CI 6.23-23.9) for MSH2 and 13.74 for MSH6 (95% CI 5.93-27.08). CONCLUSIONS: Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA-threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Detecção Precoce de Câncer , Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Noruega/epidemiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/sangue , Antígeno Prostático Específico/sangue , Pessoa de Meia-Idade , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Prospectivos , Detecção Precoce de Câncer/métodos , Idoso , Adulto , Proteína 2 Homóloga a MutS/genética , Incidência , Reparo de Erro de Pareamento de DNA/genética , Gradação de Tumores , Proteínas de Ligação a DNA/genética
19.
Cancer Prev Res (Phila) ; 17(7): 311-324, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38643981

RESUMO

Lynch syndrome (LS) is the most prevalent heritable form of colorectal cancer. Its early onset and high lifetime risk for colorectal cancer emphasize the necessity for effective chemoprevention. NFE2L2 (NRF2) is often considered a potential druggable target, and many chemopreventive compounds induce NRF2. However, although NRF2 counteracts oxidative stress, it is also overexpressed in colorectal cancer and may promote tumorigenesis. In this study, we evaluated the role of NRF2 in the prevention of LS-associated neoplasia. We found increased levels of NRF2 in intestinal epithelia of mice with intestinal epithelium-specific Msh2 deletion (MSH2ΔIEC) compared with C57BL/6 (wild-type) mice, as well as an increase in downstream NRF2 targets NAD(P)H dehydrogenase (quinone 1) and glutamate-cysteine ligase catalytic subunit. Likewise, NRF2 levels were increased in human MSH2-deficient LS tumors compared with healthy human controls. In silico analysis of a publicly accessible RNA sequencing LS dataset also found an increase in downstream NRF2 targets. Upon crossing MSH2ΔIEC with Nrf2null (MSH2ΔIECNrf2null) mice, we unexpectedly found reduced tumorigenesis in MSH2ΔIECNrf2null mice compared with MSH2ΔIEC mice after 40 weeks, which occurred despite an increase in oxidative damage in MSH2ΔIECNrf2null mice. The loss of NRF2 impaired proliferation as seen by Ki67 intestinal staining and in organoid cultures. This was accompanied by diminished WNT/ß-catenin signaling, but apoptosis was unaffected. Microbial α-diversity increased over time with the loss of NRF2 based upon 16S rRNA gene amplicon sequencing of murine fecal samples. Altogether, we show that NRF2 protein levels are increased in MSH2 deficiency and associated neoplasia, but the loss of NRF2 attenuates tumorigenesis. Activation of NRF2 may not be a feasible strategy for chemoprevention in LS. Prevention Relevance: Patients with LS have an early onset and high lifetime risk for colorectal cancer. In this study, we show that NRF2 protein levels are increased in MSH2 deficiency and associated neoplasia, but the loss of NRF2 attenuates tumorigenesis. This suggests that NRF2 may not be a tumor suppressor in this specific context.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Proteína 2 Homóloga a MutS , Fator 2 Relacionado a NF-E2 , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Humanos , Carcinogênese/genética , Carcinogênese/patologia , Camundongos Knockout , Feminino , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino
20.
Cancer Med ; 13(7): e7041, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38558366

RESUMO

BACKGROUND: Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch-like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in a variable range of LLS-associated tumors. Moreover, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated with the implementation of tumoral MMR gene testing in routine workflows. METHODS: Here, we present the clinical characterization of 229 LLS patients. MMR gene testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥5% and ≥10%). RESULTS AND DISCUSSION: More biallelic somatic events were identified at VAF ≥ 5% than ≥10% (35.9% vs. 25.6%), although the rate of nonconcordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases.


Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Mutação em Linhagem Germinativa , Reparo de Erro de Pareamento de DNA/genética
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