In Lynch syndrome adenomas, loss of mismatch repair proteins is related to an enhanced lymphocytic response

Aims:  Lynch syndrome-associated tumours are characterized by the presence of an increased number of tumour-infiltrating lymphocytes. This enhanced lymphocytic response may be elicited by genetically altered proteins that may arise as a result of a defective DNA mismatch repair system. The aim was to investigate this hypothesis by correlating loss of mismatch repair proteins and infiltration of lymphocytes in Lynch syndrome-associated adenomas and hyperplastic polyps.
Methods and results:  Mismatch repair protein expression and the number of tumour-infiltrating lymphocytes were assessed in Lynch syndrome (41 adenomas and nine hyperplastic polyps) and in familial colorectal cancer (nine adenomas and one hyperplastic polyp). Nineteen sporadic adenomas were included as a control group. Twenty of 32 (63%) adenomas with loss of mismatch repair protein expression showed an increase in tumour-infiltrating lymphocytes. Eight adenomas (8/32; 25%) displayed many tumour-infiltrating lymphocytes, whereas most adenomas (12/32; 38%) showed a minor increase. In adenomas with mismatch repair protein expression, both sporadic and Lynch syndrome associated, not one showed an increased number of tumour-infiltrating lymphocytes. Hyperplastic polyps in Lynch syndrome patients showed neither loss of mismatch repair expression nor an increase in tumour-infiltrating lymphocytes.
Conclusions:  There is a correlation between the loss of mismatch repair proteins and the infiltration of lymphocytes in Lynch syndrome-associated adenomas.     

错配修复蛋白表达及RAS基因突变与结直肠癌临床病理特征的关系

目的 探讨结直肠癌组织中错配修复(mismatch repair,MMR)蛋白表达及RAS基因突变状态与临床病理特征的相关性.方法 采用免疫组化法检测186例结直肠癌组织中4种MMR蛋白(MSH2、MSH6、MLH1、PMS2)的表达,并采用ARMS-PCR法检测RAS基因突变状态.结果 186例结直肠癌组织中MMR蛋...     

Cancer risks by gene,age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

PurposePathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.MethodsWe conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.ResultsThere were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.ConclusionManagement guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.     

Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype

There are two well-defined pathways for colorectal carcinogenesis, the suppressor and the mutator pathways. The latter is characteristic of hereditary non-polyposis colorectal cancer (HNPCC), but can also be found in a subset of sporadic colorectal cancer (SCC) possessing distinctive clinical and pathological features, namely early age of onset, location in the right colon, poor differentiation, and a predominant mucinous component. This mutator pathway results from inactivation of mismatch repair (MMR) genes, namely MSH2 and MLH1. The aim of this study was to ascertain if abnormal MMR protein gene expression is a good indicator for identifying tumours from the mutator pathway. Seventy-six cases of SCC were studied by immunohistochemistry using two monoclonal mouse antibodies that react against MSH2 and MLH1 protein gene products. Immunoexpression was assessed both in tumour and in non-neoplastic, adjacent and distant mucosa. Microsatellite instability (MSI) was detected by evaluating the length of poly(CA) repeated sequences at seven loci, or by the detection of small unstable alleles in a poly(A) repeat - BAT-26. Except for BAT-26, in which only tumour DNA was used, MSI analysis was performed in both tumour and normal mucosal DNA. MSI was classified as high (MSI-H), low (MSI-L) or stable (MSS). Abnormal protein expression was found in 9/76 (12%) tumours. Immunohistochemistry for hmlh1 and hmsh2 detected 75% of MSI-H. There was also a highly significant correlation between the observed immunoexpression and several clinical and pathological characteristics described as the phenotypic profile of the mutator pathway, such as right-sided location (p=0.003), mucin production (p=0.008), and a peritumoural lymphoid infiltrate (p=0.009). Non-neoplastic adjacent mucosa showed normal hMSH2 expression in all cases, but in ten cases there was no hMLH1 expression in this transitional mucosa, which is known to display an alterated mucin pattern and a high proliferative rate. These results demonstrated a good correlation between hMLH1 and hMSH2 gene immunoexpression and the clinico-pathological features characteristic of the mutator phenotype and support the use of this method as a rapid and efficient way to detect tumours arising from this pathway.     

Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene

Pancreatic adenocarcinoma has been reported in kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). Medullary carcinoma of the pancreas is a recently described rare variant of pancreatic adenocarcinoma. We describe a man with colorectal carcinoma who subsequently developed pancreatic medullary carcinoma. The tumor displayed microsatellite instability and loss of expression of the mismatch repair proteins MSH2 and MSH6. Mutational analysis of the mismatch repair genes MLH1 and MSH2 demonstrated a pathogenic nonsense mutation within the MSH2 gene, which is consistent with a diagnosis of HNPCC. This report adds support to an association between HNPCC and pancreatic adenocarcinoma displaying the medullary phenotype, suggesting that medullary features in a pancreatic carcinoma may point toward a genetic cancer predisposition. To our knowledge, this is the first reported case of medullary carcinoma of the pancreas in a patient with HNPCC due to a mutation of the MSH2 gene.     

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis‐like phenotype and early onset cancer

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis‐like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12–14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis‐like group, two subjects had already developed high‐grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.     

Factors associated with preterm delivery in mothers of children with Beckwith-Wiedemann syndrome: a case cohort study from the BWS registry

Pregnancy that results in a child with Beckwith-Wiedemann syndrome (BWS) is associated with preterm delivery. Based on previous case series, we hypothesized that preterm delivery of a child with BWS was due to known risk factors for preterm delivery such as polyhydramnios and gestational hypertension. A case cohort study using the BWS Registry at Washington University School of Medicine was undertaken. Cases were pregnancies that resulted in the birth of a child with BWS, controls were pregnancies resulting in the birth of siblings without BWS. Univariate analyses of maternal complications and logistic regression to predict preterm delivery were used. Children with BWS (n = 304) were delivered preterm at a significantly higher rate than their siblings (n = 269) odds ratio 19.1 (95% CI 9.1-40.2). Polyhydramnios, gestational hypertension, and vaginal bleeding also occurred at high rates in the BWS group with odds ratios of 31.6 (95% CI 12.6-79.1), 2.4 (95% CI 1.4-4.1), and 3.9 (95% CI 2.3-6.4), respectively. In a multivariate logistic regression model within the BWS group, polyhydramnios, vaginal bleeding, and gestational hypertension were significant predictors of preterm delivery, odds ratios of 2.9 (95% CI 1.6-5.4), 2.6 (95% CI 1.3-5.0), and 5.3 (2.3-12.0), respectively. However, a significant proportion, 6.5% (18 of 277), of patients in the BWS group delivered preterm without known risk factors. Preterm delivery of a child with BWS is associated with an increased frequency of polyhydramnios, gestational hypertension, and vaginal bleeding in the mother. However, preterm delivery also occurs in the absence of these risk factors.     

Prognistic value of a study of the expression of argyrophilic nucleolar organizer region associated proteins in case of papillary thyroid cancer

The prognosis in papillary thyroid cancer (PTC) is usually good. Ten-year survival can be seen in 90-98% of patients. Immunohistochemical study (antigen K-67) ascertained that a female patient with PTC had a low number of proliferating cells, which is usually seen in the favorable course of the disease. However, in the presented case, PTC was highly aggressive and showed a significant invasive growth, provided regional and distant metastases, rapidly progressed and, despite the performed surgical treatment, the patient died due to disease progression 3 months after surgery. This discrepancy between the number of proliferating cells and the aggressive course of PTC should be explained by the high expression of argyrophilic nucleolar organizer region associated proteins nucleofozmin and nucleolin, detected by immunohistochemical study, which is known to cause an increase in the rate of a mitotic cycle rate and to promote intercellular adhesion and enhancement of invasive growth and metastatic spread. Various factors involved in the regulation of proliferation of cells and their capacity for invasion and metastasis should be studied to make the most objective estimation of the degree of malignancy of a tumor and its prognosis.     

Sporadic colorectal cancers with defective mismatch repair display a number of specific morphological characteristics: relationship between the expression of hMLH1 and hMSH2 proteins and clinicopathological features of 273 adenocarcinomas

AIMS: The aim of this study was to assess the independent value of pathological criteria in the diagnosis of mismatch repair (MMR)-defective sporadic colorectal cancers. METHODS AND RESULTS: Resected colorectal adenocarcinomas (n = 273) were reviewed in order to identify a number of specific morphological features of MMR-defective carcinomas. Of the 273 cases, 35.2% were right-sided and 5.9% were poorly differentiated. Focal extracellular mucin secretion was seen in 5.1% of cases and a stromal follicular reaction in 4.6%. The expression of the two major MMR proteins hMLH1 and hMSH2 was studied by immunohistochemistry. Carcinomas were considered deficient in the MMR system when a loss of nuclear signal in neoplastic cells was observed for one of the proteins. Such an extinction was seen in 37 of the cases (13.6%). The hMLH1 protein was the one most frequently altered (86.5%). After multivariate analysis, three independent factors were significantly associated with MMR deficiency: proximal location [odds ratio (OR) = 9.30; 95% confidence interval (CI) 2.79, 30.98], the presence of a true stromal follicular reaction (OR = 13.60; 95% CI 2.98, 62.00) and poor differentiation (OR = 8.33; 95% CI 1.63, 40.32). CONCLUSIONS: These results confirm that sporadic colorectal MMR-defective adenocarcinomas display certain specific morphological characteristics. However, these pathological features are not sufficiently predictive and immunohistochemistry is needed to identify such tumours accurately.     

The 1396del A mutation and a missense mutation or a rare polymorphism of the WRN gene detected in a French Werner family with a severe phenotype and a case of an unusual vulvar cancer. Mutations in brief no. 136. Online

The Werner's syndrome (WS) is a rare recessive disease characterized by an early onset of geriatric disorders. The Werner's syndrome gene (WRN) recently cloned, encodes for an helicase and therefore plays a role in DNA metabolism and DNA repair. Here, we report the study of a French family with two affected members and numerous cancers. Using the protein truncation test and sequencing, we identified a homozygous mutation in the WRN gene. This mutation generates a frame shift leading to a very short 391 amino acids truncated protein without the helicase motif. A particularly severe phenotype of the affected patient was associated with an unusual vulvar cancer traditionaly observed in elderly patients and therefore likely to be related to the Werner's syndrome. An additional substitution of G for A at nucleotidic position 1392 was also described. We suggest that a relation between genotype and phenotype could exist in the studied family.