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Urology Jul 2022To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome... (Review)
Review
OBJECTIVE
To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome diagnostics.
MATERIALS AND METHODS
Studies were identified through PubMed on December 1, 2021. Eligibility criteria were universal immunohistochemical analyses for at least 2 MMR proteins in unselected, consecutively collected UTUC cohorts. Exclusion criteria included reviews, case-reports, non-English language, and non-humans. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Meta-analyses were performed to compare the association between clinical criteria and Lynch syndrome diagnoses.
RESULTS
From 12 included studies, 1628 surgically removed UTUC from 1626 patients were screened for MMR protein loss. In 11 studies, 140 of the 1559 patients had tumors with loss (9.0%) with 80.7% showing loss of MSH2, MSH6, or both. In 7 studies, genetic testing confirmed Lynch syndrome diagnosis for 20 of 970 patients (2.1%). In 8 studies, 31 patients were given a clinical Lynch syndrome diagnosis (2.6%). In total, 51 assumed or verified Lynch syndrome patients were identified among 1087 patients (4.7%). Meta-analyses of 3 studies showed significant association between previous cancer diagnosis and Lynch syndrome-associated UTUC (P = .038).
CONCLUSION
Despite the few studies conducted and lack of genetic testing, current data suggests that universal screening for MMR protein loss in UTUC may result in Lynch syndrome diagnoses in 4.7%. However, for the screening to be effective for Lynch syndrome diagnostics, follow-up investigations, such as genetic testing for MMR variants, are needed.
Topics: Carcinoma, Transitional Cell; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunohistochemistry; MutL Protein Homolog 1; Urinary Bladder Neoplasms
PubMed: 35217028
DOI: 10.1016/j.urology.2022.02.006 -
Lung Cancer (Amsterdam, Netherlands) May 2023Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares... (Meta-Analysis)
Meta-Analysis Review
Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares morphological and immunohistochemical features with lung and colorectal adenocarcinoma. Few data are available on patient prognosis, possible prognostic factors and systemic approach to metastatic disease. We performed a pooled analysis and a systematic review of published lung-ETAC, along with an additional case description. Thirty-one eligible publications were identified, providing data from 126 patients. In the 127 patients overall analyzed, median overall survival (OS) was 56.0 (range 36.7-75.3) months in early-stage patients and 14.0 (range 4.5-23.5) months in those with advanced/metastatic disease. Median disease-free survival (DFS) after radical surgery was 24 (range 22.6-35.1) months. Smoking status (HR 4.304, 95% CI: 1.261-14.693, p = 0.020) and node involvement (HR 1.853, 95% CI: 1.179-2.911, p = 0.007) were the negative independent prognostic factors at multivariate analysis. As regards systemic therapies for advanced cases, no firm conclusions were drawn about the efficacy of lung cancer-oriented chemotherapy regimens as opposed to colon cancer-oriented ones. Molecular analysis of lung-ETAC revealed a relatively high mutational rate, with alterations in several druggable molecular pathways, KRAS and NRAS (31%) were the most frequently mutated oncogenes, followed by ROS1 (15%), RET (13%), BRAF (11%), EGFR (8%) and ALK (6%). Moreover, 3 (15%) out of 20 cases showed DNA mismatch repair deficiency (dMMR). In conclusion, advanced lung-ETAC patients appeared to have a better prognosis compared to other subtypes of NSCLC. Moreover, the mutational rate and microsatellite instability found in lung-ETACs suggest that a significant proportion of these patients could benefit from target therapies and immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Mutation; Proto-Oncogene Proteins; Adenocarcinoma; Adenocarcinoma of Lung; Prognosis; Lung
PubMed: 37015149
DOI: 10.1016/j.lungcan.2023.107176 -
International Journal of Gynecological... May 2022Lynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer....
OBJECTIVE
Lynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies across countries and centers. We aimed to provide evidence to inform the best approach to screening and risk reduction.
METHODS
A systematic search of the literature was conducted (Medline, Embase, PubMed). Studies evaluating the following were included: women with Lynch syndrome (by mismatch repair mutation or Amsterdam II criteria), screening methods for endometrial and/or ovarian cancer, intervention included endometrial biopsy, transvaginal ultrasound, or serum cancer antigen 125 (CA-125), outcomes evaluated were number of cancers and/or endometrial hyperplasia.
RESULTS
A total of 18 studies of Lynch syndrome carriers which screened for endometrial cancer using transvaginal ultrasound and/or hysteroscopy/endometrial biopsy revealed an incidence of 3.9% at the time of screening. Most (64.1%) endometrial cancers detected were from screening, with the balance detected in symptomatic women at the first screening visits, regular review, or between screening intervals. In mismatch repair carriers, the overall sensitivity of endometrial screening was 66.7%, and the number needed to screen ranged between 4 and 38 (median 7). The sensitivity of endometrial biopsy was 57.1% and the number needed to screen was 23-380 (median 78). The sensitivity of transvaginal ultrasound was 34.4% and the number needed to screen was 35-973 (median 170). Fourteen studies which screened for ovarian cancer using transvaginal ultrasound and/or CA-125 revealed an incidence of 1.3% at the time of screening and 42.9% of ovarian cancers were detected at asymptomatic screening. The sensitivity of ovarian screening was 54.6%, and the number needed to screen was 9-191 (median 23) in mismatch repair carriers. Thirteen studies reported 5.8% incident endometrial cancers and 0.5% ovarian cancers at time of risk reducing surgery.
CONCLUSIONS
There is limited evidence to support screening for endometrial and ovarian cancer in Lynch syndrome and data on mortality reduction are not available. Further prospective, randomized trials comparing targeted screening methods are needed. Risk reducing surgery remains the most reliable way to reduce endometrial and ovarian cancer risk in Lynch syndrome.
Topics: Carcinoma, Ovarian Epithelial; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Early Detection of Cancer; Endometrial Neoplasms; Female; Humans; Ovarian Neoplasms
PubMed: 35437274
DOI: 10.1136/ijgc-2021-003132 -
World Journal of Surgical Oncology Mar 2022Immunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC.
METHODS
We searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab.
RESULTS
Fourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00-0.04), 0.04 (95% CI 0.05-0.26), 0.27 (95% CI 0.22-0.32), and 0.44 (95% CI 0.30-0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06-0.31) and 0.50 (95%CI 0.35-0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72-0.92) and 0.30 (95% CI 0.20-0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30-0.51) and 0.04 (95% CI 0.00-0.09), respectively.
CONCLUSIONS
PD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected.
TRIAL REGISTRATION
We have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601 .
Topics: B7-H1 Antigen; Colonic Neoplasms; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prospective Studies
PubMed: 35331250
DOI: 10.1186/s12957-022-02549-7 -
Familial Cancer Apr 2023A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early... (Review)
Review
A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.
Topics: Humans; Muir-Torre Syndrome; Microsatellite Instability; Sebaceous Gland Neoplasms; Genotype; Carcinoma, Basal Cell; MutS Homolog 2 Protein
PubMed: 36418753
DOI: 10.1007/s10689-022-00319-8 -
Medicina Oral, Patologia Oral Y Cirugia... Jun 2024The DNA mismatch repair (MMR) system serves as a sophisticated guardian of the precise functioning of the human genome. Dysregulation within this system is linked to the...
BACKGROUND
The DNA mismatch repair (MMR) system serves as a sophisticated guardian of the precise functioning of the human genome. Dysregulation within this system is linked to the oncogenesis process. Reduced expression of MMR system proteins identified in salivary gland tumors (SGTs) suggests an increased risk of tumoral occurrence. This study aims to analyze the expression of MMR proteins in SGTs and discuss the relevance of this association to the development of these neoplasms.
MATERIAL AND METHODS
This review was conducted following the PRISMA guidelines and was registered in PROSPERO (CRD42023465590). A comprehensive search of the PubMed/MEDLINE, Web of Science, Scopus, Embase, and ProQuest (non-peer reviewed platform) was performed to answer the question "Do DNA MMR system proteins exhibit expression in SGTs?". The methodological quality of the selected studies was assessed using the JBI's Critical Appraisal Tool.
RESULTS
A total of 142 patients with benign SGTs and 84 with malignant SGTs were included in this review. The literature analysis showed a notable reduction in the expression of DNA MMR system proteins (hHMS2, hMLH1, hMSH3 and hMSH6) in the percentage of marked cells.
CONCLUSIONS
The reduction in the expression of the DNA MMR system proteins suggests an interesting correlation with the development of malignant and benign SGTs. Nevertheless, further investigations are warranted to better clarify the precision of measuring biomarker protein expression.
PubMed: 38907641
DOI: 10.4317/medoral.26647 -
Pharmacogenomics and Personalized... 2017The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a... (Review)
Review
BACKGROUND
The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research.
MATERIALS AND METHODS
Our 2014-2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes.
RESULTS
Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23-0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09-0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation.
CONCLUSION
Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms.
PubMed: 28260941
DOI: 10.2147/PGPM.S123808 -
Genetics in Medicine : Official Journal... May 2022Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the true prevalence of LS.
METHODS
MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
RESULTS
A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
CONCLUSION
LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Microsatellite Instability; Prevalence
PubMed: 35177335
DOI: 10.1016/j.gim.2022.01.014 -
Clinical and Translational... Jul 2017Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower...
OBJECTIVES
Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome. However, the association of low-penetrance polymorphisms of DNA repair genes with CRC risk remains unclear.
METHODS
A systematic literature review of PubMed, Embase, and HuGENet databases was conducted. Pre-specified criteria determined study inclusion/exclusion. Per-allele, pooled odds ratios disclosed the risk attributed to each variant. Heterogeneity was investigated by subgroup analyses for ethnicity and tumor location; funnel plots and Egger's test assessed publication bias.
RESULTS
Sixty-one polymorphisms in 26 different DNA repair genes were identified. Meta-analyses for 22 polymorphisms in 17 genes revealed that six polymorphisms were significantly associated with CRC risk within BER (APE1, PARP1), NER (ERCC5, XPC), double-strand break (RAD18), and DRR (MGMT), but none within MMR. Subgroup analyses revealed significant association of OGG1 rs1052133 with rectal cancer risk. Egger's test revealed no publication bias.
CONCLUSIONS
Low-penetrance polymorphisms in DNA repair genes alter susceptibility to CRC. Future studies should therefore analyze whole-genome polymorphisms and any synergistic effects on CRC risk.Translational impact:This knowledge may enhance CRC risk assessment and facilitate a more personalized approach to cancer prevention.
PubMed: 28749454
DOI: 10.1038/ctg.2017.35 -
Oncology Letters Apr 2024Immune checkpoint inhibitors (ICIs) have limited efficacy in mismatch repair proficient (pMMR) or metastatic microsatellite stable (MSS) advanced or metastatic...
Effectiveness of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in patients with advanced or metastatic colorectal carcinoma with either mismatch repair proficient or metastatic microsatellite stable disease: A systematic review and meta‑analysis.
Immune checkpoint inhibitors (ICIs) have limited efficacy in mismatch repair proficient (pMMR) or metastatic microsatellite stable (MSS) advanced or metastatic colorectal cancer (mCRC). ICIs, in conjunction with tyrosine kinase inhibitors (TKIs) possessing anti-angiogenic properties, serve as a potential strategy for circumventing the resistance exhibited by MSS or pMMR mCRC to immunotherapeutic interventions. The present study aimed to evaluate efficacy and safety of ICIs + TKIs and provide a reference for the treatment of CRC. The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane, Web of Science and ClinicalTrials.gov databases were screened from January 1, 2003 to July 28, 2023. A total of 14 studies were included in qualitative and quantitative analyses, with a total of 819 patients enrolled. The Newcastle-Ottawa scale scores of the 14 cohort studies included were ≥7, indicating they were of a high quality. The objective response rate (ORR) of ICIs + TKIs was 14% [95% confidence interval (CI), 0.08-0.24; P=0.132] in patients with advanced or metastatic MSS/pMMR CRC. The disease control rate (DCR) was 65% (95% CI, 0.58-0.74; P<0.0001). The overall incidence of adverse events of varying severity linked to combination of ICIs and TKIs in patients with advanced or metastatic MSS/pMMR CRC was 64% (95% CI, 0.52-0.78; P<0.0001). The incidence of grade ≥3 adverse reactions was 24% (95% CI, 0.14-0.4; P<0.0001). The sensitivity analysis indicated that the exclusion of individual studies did not yield statistically significant variations in combined analysis results. Based on the examination of publication bias, ORR and DCR, Begg's and Egger's tests had P-values of 0.114 and 0.395, respectively. Overall publication bias overall was absent in the Begg's funnel plot, as there was no apparent asymmetry. Nonetheless, the P-values of the Egger's and Begg's tests for adverse reactions and adverse reactions grade ≥3 were P=0.008 and P=0.048, respectively. The asymmetry of the Begg's funnel plots was evident, suggesting the presence of potential publication bias regarding adverse event results. In conclusion, the combination of ICIs and TKIs demonstrates a favorable effectiveness and notable safety profile in the management of patients with advanced or metastatic MSS/pMMR CRC.
PubMed: 38406596
DOI: 10.3892/ol.2024.14286