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Distribution of the mismatch repair mutations in HNPCC patients with SBCs
Source publication
The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC).
A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regardi...
Contexts in source publication
Context 1
... we analyzed the distribution of MSH2 mutations in the DNA-binding domain, the MSH3/MSH6 interaction domain, the MutL homologue interaction domain, and a region that had no known function (codons 626-733; ref. 11). Fourteen of 34 mutations were found in the DNA binding domain Table 1, the distribution of MLH1 mutations did not differ between the experimental and control groups (P = 0.44), but the distribution of MSH2 mutations found in HNPCC patients with SBCs was significantly different from that in the control group (P < 0.001). Patients with SBCs had less frequent mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019, Fisher's exact test), but more frequent mutations in codons 626 to 733 (26.5% versus 2.8%, P < 0.001, Fisher's exact test). ...
Context 2
... were no significant differences in the mutational frequencies of the DNA-binding and MSH3/MSH6 interaction domains of MSH2. In Table 1, we determined the frequency of mutations in each functional domain of the MLH1 and MSH2 genes and compared this distribution with those in a control group derived from the International Society for Gastrointestinal Hereditary Tumours database. Thus, the data are presented in terms of the number of different germline mutations not families or individual cases. ...
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Citations
... SBA is often associated with advanced age, inflammatory bowel disease (IBD), and coeliac disease. However, it can also be caused by specific inheritable syndromes such as familial adenomatosis polyposis (FAP) syndrome, Lynch syndrome, and MUTYH-associated polyposis (MAP) [4][5][6][7]. ...
(1) Background: Small bowel adenocarcinoma (SBA) is one of the predominant primary small bowel cancers that has a dismal outcome. We aim to report 10 years of experience in SBA management at a regional cancer centre in Canada.; (2) Methods: We retrospectively analysed clinical and pathological data of patients diagnosed with an SBA between 2011 and 2021 at the Ottawa Hospital (TOH), Ottawa, Canada. We describe the clinicopathological features and outcomes, including survival. Potential prognostic factors were analysed using the Cox proportional hazard model for multivariate analysis.; (3) Results: We identified 115 patients with SBA. The duodenum was the most common SBA location representing 61% (70) of the total patients, followed by the jejunum (17%) and ileum (10%). Around 24% (27) of cases presented with bowel obstructions. The majority of patients (56%, 64) had stage IV disease on presentation. Seven patients had MSI-high tumours, while 24% (27) were MS-stable. In terms of management, 48 patients underwent curative surgical resection, 17 of whom received adjuvant chemotherapy. On the other hand, 57 patients (49.5%) with the advanced disease received palliative systemic therapy, and 18 patients (16%) had supportive care only. Over a median follow-up of 21.5 months (range 0–122), the median overall survival was 94, 61, and 34 months for stages II, III, and IV, respectively (p < 0.05). The median recurrence-free survival was 93 and 23 months for stages II and III, respectively. However, there was no statistically significant difference between TNM stages in RFS, p = 0.069. Multivariate Cox regression analysis showed only poor performance status at diagnosis as a predictor for shorter overall survival (p < 0.05). The univariate analysis didn’t show any significant correlation between RFS and covariants.; (4) Conclusions: SBA remains one of the most aggressive tumours with a dismal prognosis even after surgical resection. The optimal chemotherapy regimen has not been established. Further studies are needed to explore the role of adjuvant chemotherapy for stages I-III SBA.
... The median age of SBA diagnosis in LS patients ranged from 39 to 53 years [48][49][50]. Adenocarcinoma has been found in a large majority of cases (81% to 100%) [50,51]. It has also been suggested that LS-related SBA has a better prognosis than sporadic SBAs [47]. ...
Lynch syndrome patients could benefit from various recommendations to prevent digestive cancers. In this review, we summarize the criteria to identify Lynch syndrome in patients with digestive cancers. We detail endoscopic screening procedures in patients with Lynch syndrome for gastric, small bowel, pancreatic, and colorectal cancers. We review the precise modalities of endoscopic follow-up, particularly the discrepancies that exist between the guidelines of the various scientific societies. We discuss the treatment of colorectal cancers in Lynch syndrome cases and patient adherence to endoscopic follow-up programs.
... Numerous case series have described small bowel cancers in LS patients and demonstrated that these neoplasms can be the first and only cancer in this syndrome. Moreover, these patients may develop malignancy as soon as the early teens and most tumors are located in the duodenum or the jejunum [104,105]. The pathologist may have an important role in identifying LS patients through the routine use of MMR immunohistochemical analysis and MSI testing in both precursor lesions and cancers of the small bowel. ...
The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, MUTYH-associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn's disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn's disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions.
... The basic function of mismatch repair is to remove the insertion/deletion loop caused by base mismatch and DNA polymerase slide in the process of replication, correct the recombination of non-homologous chromosomes and maintain the stability of the whole genome [10] . Frequent DNA replication errors can cause changes in the microsatellite sequence of cells, which is manifested by the length increase or decrease of microsatellite fragments, which is de ned as microsatellite instability (MSI), a speci c phenotype of mismatch repair system functional defects [11,12] . In patients with colorectal cancer, dMMR/MSI patients have unique clinical pathological features, including early onset, high incidence in the right hemicolon, mostly mucinous adenocarcinoma and poorly differentiated adenocarcinoma in histological types, presence of Crohn's like lymphocyte reaction, and good prognosis [13] . ...
Background: Ovarian clear cell carcinoma (OCCC) is a distinct subtype of epithelial ovarian cancer. With the exception of very early stage disease, OCCCs are associated with worse prognosis due to poor response to platinum-based chemotherapy compared with serous carcinoma. OCCCs with microsatellite instability (MSI) may represent a unique subset and may open an alternative therapeutic avenue for a fraction of patients with OCCC. The purpose of this study is to explore the role of DNA mismatch repair (MMR) in the genesis and development of clear cell carcinoma by determining the differential expression of MMR gene in different subtypes of ovarian carcinoma and the expression of MMR protein in clear cell carcinoma, so as to provide ideas for future tumor treatment.
Results: The expression of MSH6 gene in HGSC group was higher than that in OCCC group, and the difference had statistical significance (P=0.01). The expression of MLH1 gene in OCCC group was higher than that in HGSC group, and the difference had statistical significance (P=0.0221). There was no significant difference in the expression of MSH2 gene between the two groups. There were no significant differences in the expression of the three genes between OCCC group with good prognosis (group G) and OCCC group with poor prognosis (group P). In order to further verify the expression of MMR protein in OCCC group, immunohistochemistry was performed, and the results showed that 92.3% of the patients (36/39) had pMMR, 7.69% of the patients (3/39) had dMMR. The average follow-up time of patients with dMMR was 19.3 months, and there was no recurrence or death.
Conclusion: There were differences in the expression of MSH6 and MLH1 genes between ovarian clear cell carcinoma and high-grade serous carcinoma, indicating that the two subtypes of tumor may have different origins. The prognosis of clear cell carcinoma patients with dMMR was better as of the follow-up date, suggesting that dMMR may be an early event of clear cell carcinoma.
... The median age of diagnosis varied from 39 to 53 years [77 -83]. The majority of the small-bowel cancers were located in the duodenum or jejunum [77 -82] and histology showed adenocarcinoma in 81 % to 100 % of the cases [79,81]. ...
Main Recommendations
ESGE recommends that individuals with Lynch syndrome should be followed in dedicated units that practice monitoring of compliance and endoscopic performance measures.
Strong recommendation, low quality evidence, level of agreement 100 %.
ESGE recommends starting colonoscopy surveillance at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers.
Strong recommendation, moderate quality evidence, level of agreement 100 %.
ESGE recommends the routine use of high-definition endoscopy systems in individuals with Lynch syndrome.
Strong recommendation, high quality evidence, level of agreement 100 %.
ESGE suggests the use of chromoendoscopy may be of benefit in individuals with Lynch syndrome undergoing colonoscopy; however routine use must be balanced against costs, training, and practical considerations.
Weak recommendation, moderate quality evidence, level of agreement 89 %.
ESGE recommends definition of familial risk of colorectal cancer as the presence of at least two first-degree relatives with colorectal cancer or at least one first-degree relative with colorectal cancer before the age of 50 years.
Strong recommendation, moderate quality evidence, level of agreement 92 %.
ESGE recommends colonoscopy surveillance in first-degree relatives of colorectal cancer patients in families that fulfill the definition of familial risk of colorectal cancer.
Strong recommendation, moderate quality evidence, level of agreement 100 %.
... Le domaine D6 contient le motif TRG (translocation in RecG) de 37 acides aminés homologue à RecG et nécessaire aux fonctions des deux protéines. Chez TRCF, ce motif TRG serait responsable de l'activité translocase déclenchée après l'interaction avec la 72 RNAP bloquée, permettant son dégagement en tirant l'ADN à travers la RNAP (Park et al., 2006). ...
La mitochondrie et le chloroplaste possèdent un génome dont l’expression et la maintenance dépendent de facteurs codés par le génome nucléaire. L’ADN mitochondrial des plantes (ADNmt) est caractérisé par d’importantes activités de recombinaison qui modulent sa structure et contribuent à son évolution. Au cours de ma thèse, j’ai caractérisé l’hélicase RADA qui est impliquée dans les étapes tardives de la recombinaison homologue organellaire. RADA possède des fonctions similaires à son homologue bactérien (RadA), mais semble jouer un rôle plus important dans les organelles de plantes. L’expression du génome chloroplastique (ADNcp) repose sur deux types d’ARN polymérases : la NEP, codés par le génome nucléaire et la PEP, codés par l’ADNcp. Durant ma thèse, j’ai également étudié le rôle de TRCF, homologue du facteur Mfd et adressé aux chloroplastes. Chez les bactéries, Mfd est impliqué dans le dégagement des ARN polymérases bloquées par des lésions et le recrutement de facteurs de réparation. Chez Arabidopsis, TRCF n’est plus impliqué dans la réparation, mais semble jouer un rôle dans la régulation de l’expression des gènes chloroplastiques.
... To date, various molecules are used in cancer diagnosis, prediction of outcome, and therapy. They include mismatch repair genetic mutations in hereditary colorectal cancer [4], Ki67 in neuroendocrine tumors [5], and c-kit mutations in gastrointestinal stromal tumors [6]. ...
Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC), representing an advanced disease stage and independently predicting patient survival. Current nodal staging is inadequate preoperatively and even less so postoperatively, and molecular biomarkers are needed to improve prognostication and selection of therapy. Recent data have suggested important roles of miRNAs in PDAC tumorigenesis and progression. The aim of the present study was to identify miRNA expression signature for nodal spread in PDAC patients. Using PDAC human tissue specimens, we identified 39 miRNAs which were differently expressed in LN positive compared to LN negative PDAC samples. Of them, six miRNAs have been reported to play a role in cancer invasion and metastasis. A high versus low six- miRNA signature score was predictive of LN metastasis in the PDAC validation cohort. We demonstrated a similar expression pattern of four out of the six miRNAs in the plasma of PDAC patients. The results of our in-vitro studies revealed that miR- 141 and miR-720 are involved in the process of epithelial to mesenchymal-transition in PDAC. These miRNAs significantly inhibited in vitro proliferation, migration and invasion of PDAC cells as evidence by gain- and loss- of function studies, specifically, via ZEB-1 and TWIST1 transcription factors, as well as through the activation of the MAP4K4/JNK signaling pathway.
... [77][78][79][80][81][82] In regards to genotype, the incidence appears to be similar in MLH1 and MSH2 mutation carriers, whereas in MSH6 and PMS2 mutation carriers it is significantly low. 72,79 However, international guidelines 21,46,61 do not recommend SB surveillance. ...
Despite its rarity in the general population, small bowel adenocarcinoma risk is increased in individuals with hereditary colorectal cancer syndromes (HCCS). In the last decade, the advent of capsule endoscopy and device-assisted balloon enteroscopy procedures in patients with HCCS have allowed to investigate the whole small bowel, increasing the diagnostic yield of small bowel tumor. Nonetheless, there is a significant variability in the international guideline recommendations. The aim of this review is to provide an update on surveillance of small bowel in HCCS and to identify the key points for the clinical management of these patients.
... Hypothesis for the retained protein expression in the small one is that complete loss of MMR function requires multiple cell cycle alterations and could be a late event in the neoplastic transformation (9). Small intestine tumors account for fewer than 2% of gastrointestinal tract tumors in the general population (11). There are several inherited syndromes that increase the likelihood of developing this condition, such as familial adenomatous polyposis (FAP) disease, Peutz-Jeghers disease and LS (11,12). ...
... Small intestine tumors account for fewer than 2% of gastrointestinal tract tumors in the general population (11). There are several inherited syndromes that increase the likelihood of developing this condition, such as familial adenomatous polyposis (FAP) disease, Peutz-Jeghers disease and LS (11,12). In LS, the probability of small intestine carcinoma ranges from 1-4%, around 100 times higher than in the general population (11,12). ...
... There are several inherited syndromes that increase the likelihood of developing this condition, such as familial adenomatous polyposis (FAP) disease, Peutz-Jeghers disease and LS (11,12). In LS, the probability of small intestine carcinoma ranges from 1-4%, around 100 times higher than in the general population (11,12). Adenocarcinomas are the most common type (as in our patient), with one reported case of carcinoid-type neuroendocrine tumor. ...
Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and sebomatricoma. With the exception of one P-NET, all these conditions were associated with LS, as confirmed by immunohistochemistry (IHC) and polymerase chain reaction (PCR). LS is caused by a mutation of a mismatch repair (MMR) gene which leads to a loss of expression of its protein. CRC is the most common tumor, followed by EC. Pancreatic tumors have also been associated with LS. Diagnosis of LS is based on clinical criteria (Amsterdam II and Bethesda) and genetic study (MMR gene mutation). The association between LS and our patient's tumors was confirmed by IHC (loss of expression of proteins MLH1 and its dimer PMS2) and the detection of microsatellite instability (MSI) using PCR.
... In proven CRC, MMR status is a very important risk and prognostic measurement [49][50][51][52]. Despite MSI is a crucial risk factor for MPCs in the sporadic CRC [30,32], the majority of studies were to determine the association between MSI and MPCs in HNPCC [53][54][55][56][57]. Thus, no reliable systematic data to unravel the mystery that whether MSI can predicts the risk of MPC in sporadic CRC patient. ...
Microsatellites instability (MSI) is a risk factor for multiple primary cancers (MPCs). However, a variety of studies focused on the risk in the hereditary non-polyposis colorectal cancer (HNPCC) not the sporadic colorectal cancer (CRC) patients. The aim of this meta-analysis was to comprehensive overview and quantitative summary the association between MSI and risk of MPCs. A comprehensive literature search in MEDLINE, EMBASE, Web of science, ScienceDirect, Weily and OVID was conducted. Up to May 2016, we identified 22 observational studies. We calculated the summary relative risk (RR) for the risk of MPCs in MSI patients compared with microsatellites stability (MSS) patients using fixed- or random-effects models. The RR of the association between mismatch-repair gene (MMR) genotype and MPCs was 2.59 (95% confidence interval [CI], 2.06 to 3.27); the RR was 2.14 (95% CI, 1.78 to 2.57) for sporadic CRC and 5.59 (95% CI, 2.69 to 11.59) for HNPCC for the MSI versus MSS category. The subgroup analyses showed different mutant gene, mutant locus, and mutant level of MMR with different influence on the patients susceptible to MPCs. In addition, MSI genotype increase the risk of MPC was not associated with an apparently specific in regard to site, timing, age and detection method. In conclusion, this meta-analysis indicates that MSI is associated with an increased risk of MPCs both in the HNPCC and sporadic CRC patients. Our findings will form the backbone of the treatment for MSI genotype may be an important valuable strategy for MPCs prevention.
