Hereditary Nonpolyposis Colorectal Carcinoma Research Articles

Expression status of MLH1 and MSH2 mismatch repair proteins in colorectal carcinoma

Abstract Background Colorectal carcinoma (CRC) is a main cause of morbidity and mortality worldwide. Lynch syndrome or hereditary nonpolyposis colorectal carcinoma is a cancer syndrome that accounts for 5–10% of cases of CRCs, and it is caused by a germline mutation in one or more of mismatch repair (MMR) genes, that is, MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog (PMS2), and epithelial cellular adhesion molecule. Nearly 90% of cases have mutations in either MLH1 or MSH2 gene. Aim To study the immunohistochemistry of MLH1 and MSH2 MMR proteins in CRC and to study the association of abnormal MMR protein expression with clinicopathological parameters. Patients and methods This study included 48 cases of consecutive colectomy specimens submitted to the Pathology Department of Al-Azhar University hospitals and some private laboratories. The patients’ age ranged between 22 and 81 years (median, 53 years), and 35 (72.9%) cases were male and 13 (27.1%) cases were females. Results Among the 48 studied CRC cases, 11 (22.9%) cases were MMR deficient, whereas 37 (77.1%) cases were MMR proficient. MMR defects owing to germline mutations of MSH2 were eight (72.7%) cases of the MMR deficient and that due to the functional missense mutation or hypermethylation of MLH1 were three (27.3%) cases. Conclusions Immunohistochemistry for MLH1 and MSH2 is a rapid, reliable, effective, and relatively inexpensive method to detect MMR deficiency in CRC tumors. The patterns of expression of MMR protein demonstrated distinct associations with right-sided mucinous colon carcinoma and high tumor grade, which may be valuable for prognosis and clinical treatment of CRCs.

Changes in the Transcriptome Caused by Mutations in the Ribosomal Protein uS10 Associated with a Predisposition to Colorectal Cancer.

A number of mutations in the RPS20 gene encoding the ribosomal protein uS10 have been found to be associated with a predisposition to hereditary non-polyposis colorectal carcinoma (CRC). We transfected HEK293T cells with constructs carrying the uS10 minigene with mutations identical to those mentioned above and examined the effects of the produced proteins on the cellular transcriptome. We showed that uS10 with mutations p.V50SfsX23 or p.L61EfsX11 cannot be incorporated into 40S ribosomal subunits, while the protein with the missense mutation p.V54L functionally replaces the respective endogenous protein in the 40S subunit assembly and the translation process. The comparison of RNA-seq data obtained from cells producing aberrant forms of uS10 with data for those producing the wild-type protein revealed overlapping sets of upregulated and downregulated differently expressed genes (DEGs) related to several pathways. Among the limited number of upregulated DEGs, there were genes directly associated with the progression of CRC, e.g., PPM1D and PIGN. Our findings indicate that the accumulation of the mutant forms of uS10 triggers a cascade of cellular events, similar to that which is triggered when the cell responds to a large number of erroneous proteins, suggesting that this may increase the risk of cancer.

Mutator Phenotype in a Subset of Chronic Lymphocytic Leukemia

The replication error phenotype (RER+), characterized by widespread microsatellite instability, is an important feature of tumors from patients with hereditary nonpolyposis colorectal carcinoma (HNPCC). This widespread instability affects repeat tracts of all lengths and is usually attributed to mutations of critical mismatch repair genes. Recently, several reports described occasional microsatellite alterations in tumors not associated with HNPCC. However, a true mutator phenotype (RER+) is very rare outside of HNPCC-associated malignancies. We examined 29 cases of chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world for evidence of microsatellite instability. We identified a mutator phenotype in (2/29) 7% of the cases studied. These data suggest that the mismatch repair pathway may be altered in at least a subset of patients with CLL.

Immunohistochemical Expression of MMR Proteins with Clinicopathological Correlation in Colorectal Cancer in Egypt.

BACKGROUND:Microsatellite instability (MSI) is the genetic pathway underlying 15% of sporadic colorectal carcinoma (CRC) and hereditary non-polyposis CRC. MSI-H CRC has a distinct clinicopathological characteristic including excess mucin and signet ring component, proximal colon, Crohn’s like reaction, lymphocytic infiltration, and better survival.AIM:This research aims to screen Egyptian CRC patients for MSI status by IHC testing of expression of the MMR proteins in correlation to its clinicopathological features.MATERIAL AND METHODS:Immunohistochemistry study for mismatch repair proteins (MMR) was done on 115 cases of CRC. Their expressions were assessed and correlated to clinicopathological parameters in an attempt to obtain the most significant predictors of MSI.RESULTS:MSI (low and high) represents 67% of the study cases. The most frequent expression pattern was combined loss of MLH, and PMS2 (38% of MSI) followed by a combined loss of MSH2, and MSH6 (29% of MSI). There was significant correlation of expression pattern of MMR proteins with the laterality, lymphovascular emboli, perineural invasion, grade, T stage, N stage, signet ring component, tumor infiltrating lymphocyte, and peritumoral lesion (0.014, 0.035, 0.012, 0.033, 0.013, 0.000, 0.041, 0.012, and 0.009 respectively). Proximal location (right sided) and lower grade, higher nodal stage, and marked TIL were selected as predictors of MS-H CRC (0.005, 0.031, 0.025, and 0.000 respectively).CONCLUSION:All clinicopathological and histological parameters should be assessed in CRC for the sake of predicting MSI. The optimal approach to MSI evaluation is (IHC) assessment of MMR proteins.

Association of Polymorphism GST1 Gene and Antioxidant status, and Interleukin-17 of Colorectal Cancer Iraqi Patients

Colorectal cancer account as the third frequent carcinoma worldwide. It is expected that most cases of CRC occur sporadically (70–80%), while around 15% of CRC case resulted from inherited factors, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal carcinoma (HNPCC). A total of (60) samples collected from Gastroenterology and Liver diseases teaching hospital from April 2018 to July 2018. The aim of this present study to was to detect association of polymorphism GST1 gene (on chromosome 20) with the risk of cancer Iraq patients and compare between GST1 gene of Iraq population with gene bank of NCBI. Examine oxidative stress and antioxidant status, and Interleukin-17 of Colorectal cancer patients. A significant decrease in the IL-17A and MDA levels were showed in control compared to patients. The levels of GSH show a highly significant change in control compared to patients. The results show substitution three Transversion G>C, one Transition G>A of GST1gene and showed 99% identified with a standard in Gene Bank from patients group while having 100% identified with a standard in Gene Bank with the control group.

Adenocarcinoma of the Colon and Microsatellite Instability

This image shows colon adenocarcinoma in the cecum. Which statement about colorectal adenocarcinomas is most accurate?a.Only sporadic colorectal adenocarcinomas can be associated with microsatellite instabilityb.Only colorectal carcinomas associated with the Lynch syndrome (hereditary nonpolyposis colorectal carcinoma) are associated with microsatellite instabilityc.Colorectal carcinomas are the only carcinomas associated with microsatellite instabilityd.Carcinomas of various sites—colon, rectum, and endometrium among others—can have microsatellite instability Answer: d. Carcinomas of various sites—colon, rectum, and endometrium among others—can have microsatellite instability.1Chang L. Chang M. Chang H.M. Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy.Appl Immunohistochem Mol Morphol. 2018; 26: e15-e21Crossref PubMed Scopus (187) Google Scholar Microsatellite instability is a characteristic feature of the Lynch syndrome (hereditary nonpolyposis colorectal carcinoma) but can also occur somatically in sporadic colorectal carcinomas.1Chang L. Chang M. Chang H.M. Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy.Appl Immunohistochem Mol Morphol. 2018; 26: e15-e21Crossref PubMed Scopus (187) Google Scholar

Therapy-associated myelodysplastic syndrome with monosomy 7 arising in a Muir-Torre Syndrome patient carrying SETBP1 mutation.

Muir-Torre Syndrome (MTS) is a rare hereditary autosomal dominant cancer syndrome and is linked to hereditary non-polyposis colorectal carcinoma (Lynch Syndrome). Individuals develop various skin neoplasms in addition to colorectal, endometrial and upper gastrointestinal malignancies. Therapy-associated myelodysplastic syndrome (T-MDS) is an aggressive hematologic malignancy and is considered a pre-leukemic phase. T-MDS is associated with prior exposure to chemo- and radiotherapy that potentially results in DNA damage. The current case report presents a 74-year-old male MTS patient with prior history of solid tumors and radiation therapy with new onset cytopenia. A subsequent bone marrow biopsy revealed multilineage dysplasia with a high blast count and a diagnosis of high grade T-MDS was rendered. FISH and G-banded karyotype analyses revealed 5q deletion and monosomy 7. This is a unique case of T-MDS arising in the setting of MTS. Secondary malignancies including MDS and acute leukemia may occur in cancer survivors and are often associated with an unfavorable prognosis. This case demonstrates the need to be aware of the risk of secondary hematologic malignancies in cancer patients and a thorough clinical and lab work-up are warranted in patients with persistent or transfusion requiring cytopenia(s).

Significance of the monitoring and screening for hereditary nonpolyposis colorectal carcinoma syndrome patients by presenting a case of a family tree

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering. We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years. To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out. A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969-970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182-1187.

Evaluation of clinical and histological criteria and outcome in management of hereditary non-polyposis colorectal carcinoma (HNPCC).

e14552 Background: Lynch syndrome, or HNPCC, is the most common inherited colorectal carcinoma (CRC) syndrome accounting for 2-5% of all cases. Pathologists initiate IHC testing based on patient ag...

Germline Mutation of RPS20, Encoding a Ribosomal Protein, Causes Predisposition to Hereditary Nonpolyposis Colorectal Carcinoma Without DNA Mismatch Repair Deficiency

Little is known about the genetic factors that contribute to familial colorectal cancer type X (FCCX), characterized by hereditary nonpolyposis colorectal carcinoma with no mismatch repair defects. Genetic linkage analysis, exome sequencing, tumor studies, and functional investigations of 4 generations of a FCCX family led to the identification of a truncating germline mutation in RPS20, which encodes a component (S20) of the small ribosomal subunit and is a new colon cancer predisposition gene. The mutation was associated with a defect in pre–ribosomal RNA maturation. Our findings show that mutations in a gene encoding a ribosomal protein can predispose individuals to microsatellite-stable colon cancer. Evaluation of additional FCCX families for mutations in RPS20 and other ribosome-associated genes is warranted.

An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms

Lynch syndrome, originally described in 1913 and previously known as hereditary nonpolyposis colorectal carcinoma syndrome, is the most common hereditary cancer syndrome. This syndrome is classically due to germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. The cancer risk for patients with Lynch syndrome is not limited to the colorectum; women with Lynch syndrome are at risk for endometrial cancer, and Lynch patients of both genders are at risk for other cancers as well. There are cases of cancers in families that meet the clinical criteria (Amsterdam and Bethesda criteria) for Lynch syndrome but do not have a mutation in the one of the four classic mismatch repair genes. For some time, there has been speculation that other mutations or mechanisms were responsible for a subset of Lynch syndrome patients; much research has gone into identifying those alternative mutations and mechanisms. Recently, EPCAM deletion, CHEK2 mutations, and germline MLH1 hypermethylation have been identified as alternative mutations that cause Lynch syndrome in mismatch repair-negative patients. This article reviews these novel mechanisms and mutations, their clinical significance, and the pathogenesis of these Lynch causing mutations.

Muir-Torre-Syndrom mit bisher nicht beschriebener Frameshift-Mutation im MSH2-Gen

Muir-Torre syndrome (MTS) is a rare phenotypic variant of hereditary non-polyposis colorectal carcinoma (HNPCC, Lynch syndrome), in which patients, in addition to visceral carcinomas, develop skin tumors. Multiple keratoacanthomas and basal cell carcinomas with sebocytic differentiation are characteristic as well as multiple benign and malignant tumors of the sebaceous glands, such as sebaceous adenoma, sebaceous epithelioma (sebaceoma) and sebaceous carcinoma. Particularly Cystic tumors of the sebaceous glands are especially suggestive of MTS. In genetically predisposed persons, cutaneous and visceral tumors are diagnosed at an average age of 53 years. Here we present an interesting case of a 65-year-old man in whom molecular genetic tests revealed a novel mutation in the MSH2 gene, leading to a frame shift within the gene.

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Descriptive characteristics of a colon disease family registry at an urban hospital

Background: Hospital registries are an important component of cancer screening efforts of individuals and communities. This paper describes the structure and goals of a Colon Disease Family Registry at a metropolitan hospital. Patient characteristics, differences between gastrointestinal diseases among probands, subjective distress in relation to perception of colorectal cancer, and quality of life were examined. Methods: Participants were patients with colorectal cancer (CRC), familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal carcinoma (HNPCC) and inflammatory bowel disease ulcerative colitis (UC) and Crohn's disease representing a range of colonic diseases. A total of 630 probands were recruited into the registry and administered a questionnaire. Results: Of the 630 probands, 198 (31.4%) were diagnosed with CRC, 36 (5.3%) with FAP or HNPCC and 272 (43.2%) with UC or Crohn's. The majority of all three groups had some level of college education, was white, and reported a household income greater then $70,000. The Impact of Event Scale score was found to be of notable significance when categorized by relation to proband ( p < 0.01) and proband diagnoses ( p ≤ 0.000). On the quality of life item, the largest difference was between FAP or HNPCC and UC or Crohn's without CRC. Conclusion: Subjective distress scores were higher for CRC probands in comparison to probands with other colorectal diseases. Quality of life was relatively high for all probands. Psychological distress should be explored in more depth and more frequently to screen for any concomitant psychiatric disorders like post-traumatic symptoms that have been linked to a cancer diagnosis.

Small Bowel Carcinoma in Young Patient Detected by Double-balloon Enteroscopy

A 17-year old female presented with a chief complaint of melena and epigastric pain. She had a family history of colon cancer, her mother having been diagnosed with hereditary nonpolyposis colorectal carcinoma (HNPCC). After close examination including double-balloon enteroscopy, the patient was diagnosed with small bowel carcinoma, in spite of her young age. Here we report this rare case of small bowel carcinoma in a young patient with a family history of HNPCC.

Abstract AACR1-1: Synthetic Lethal Approaches to Cancer Therapy

Abstract A critical link exists between genomic instability and cancer development. This instability can manifest as small changes at the nucleotide level or as gross chromosomal alterations. Mutations in the genes that encode DNA damage response proteins are responsible for a variety of genomic instability syndromes including Hereditary Non-Polyposis Colorectal Carcinoma, Bloom syndrome, Ataxia-telangiectasia, BRCA1 and BRCA2 mutated breast and ovarian cancers and Fanconi anaemia. Similarly epigenetic silencing of genes associated with the maintenance of genomic stability have also been implicated in the pathogenesis of cancer. Here, I discuss how different tumours may be classified not only by tumour site but also by the type of underlying genetic instability. This type of classification may assist in the optimization of treatment regimens as well as informing the development of new therapeutic approaches in particular based on “synthetic lethality”. I will illustrate these principles by demonstrating potential “synthetic lethal” treatments for mismatch repair deficient cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr AACR1-1.

Endometrial carcinomas with ambiguous features

Endometrial carcinomas are a heterogenous group of tumors that show variable histologies, molecular abnormalities and clinical outcomes. The idea of rigid distinctions between tumor types is appealing to pathologists, gynecologists, researchers and patients, but in a recent study where high grade endometrial carcinomas were reviewed by three experienced gynecologic pathologists, diagnostic agreement about tumor type was reached in only approximately one half of cases. In general, biologically and clinically validated diagnostic criteria are lacking for high grade endometrial carcinomas and for those that appear mixed epithelial. Until such criteria are developed, it remains important to define which morphologic patterns convey accurate clinical and biological information and which do not or might not. "Endometrial carcinomas with ambiguous features," the focus of this review, are tumors with comparatively uninformative morphologic features. Some publications indicate that gland forming and papillary endometrial carcinomas that appear morphologically low grade or ambiguous are really high grade. There are also indications that high grade endometrial carcinomas are biologically heterogeneous and that the morphologic clues we currently use to distinguish one subtype from another fail to correlate with biological data. Many tumors that appear morphologically mixed are, in fact, not biologically or clinically confused: most represent biologically "pure" tumors with variant morphology. Interesting associations between the presence of Lynch Syndrome (hereditary nonpolyposis colorectal carcinoma syndrome) and ambiguous morphology have been discussed in the literature. An apparent relationship between morphologic ambiguity and malignant mixed Müllerian tumor (MMMT) also exists. The identity of some morphologically ambiguous endometrial carcinoma can be elucidated with immunohistochemistry or other ancillary techniques at present, but the nature of many still remains undefined. This review presents the concept of morphologically ambiguous endometrial carcinomas, proposes morphological gold standard diagnostic criteria for tumors that are not ambiguous (an effort that helps define tumors that are ambiguous), provides a relevant literature review and offers practical guidance for sorting through diagnostically challenging cases.

Primary Peritoneal Cancer After Bilateral Salpingo-Oophorectomy in Two Patients With Lynch Syndrome

Women with Lynch syndrome or hereditary nonpolyposis colorectal carcinoma (HNPCC) have a 40-60% lifetime risk of endometrial cancer and a 7-12% lifetime risk of ovarian cancer. Risk-reducing surgery, including hysterectomy and bilateral salpingo-oophorectomy (BSO), is currently recommended once child bearing is complete. We describe two cases of primary peritoneal cancer after BSO in women with Lynch syndrome or HNPCC. The first patient was a 44-year-old woman who underwent hysterectomy with BSO for benign disease. She presented 12 years later with a pelvic mass and was diagnosed with a high-grade serous primary peritoneal cancer. Genetic testing showed a mutation in the MSH2 DNA mismatch repair gene. The second case was a 58-year-old woman who had a hysterectomy and BSO for endometrial cancer. She developed a high-grade serous primary peritoneal cancer 8 years later and was found to have a mutation in the PMS2 DNA mismatch repair gene. Women with Lynch syndrome or HNPCC should be counseled that they may be at risk for developing primary peritoneal cancer despite undergoing gynecologic cancer risk-reducing surgery. The magnitude of this risk remains to be determined.

Defective Mismatch Repair, Microsatellite Mutation Bias, and Variability in Clinical Cancer Phenotypes

Microsatellite instability is associated with 10% to 15% of colorectal, endometrial, ovarian, and gastric cancers, and has long been used as a diagnostic tool for hereditary nonpolyposis colorectal carcinoma-related cancers. Tumor-specific length alterations within microsatellites are generally accepted to be a consequence of strand slippage events during DNA replication, which are uncorrected due to a defective postreplication mismatch repair (MMR) system. Mutations arising within microsatellites associated with critical target genes are believed to play a causative role in the evolution of MMR-defective tumors. In this review, we summarize current evidence of mutational biases within microsatellites arising as a consequence of intrinsic DNA sequence effects as well as variation in MMR efficiency. Microsatellite mutational biases are generally not considered during clinical testing; however, we suggest that such biases may be clinically significant as a factor contributing to phenotypic variation among microsatellite instability-positive tumors.

21. Comparative study between immunohistochemistry and microsatellite instability for screening of hereditary non-polyposis colorectal cancer syndrome

<h3>Background and Aim</h3> Screening for hereditary non-polyposis colorectal carcinoma (HNPCC) includes molecular methods to assess microsatellite instability (MSI) and immunohistochem-ical (IHC) analysis of DNA mismatch repair (MMR) proteins. We aimed to compare these approaches as screening tools in a general laboratory setting. <h3>Method</h3> All cases of colorectal carcinoma resection reported from 2006 to mid-2008 in patients aged 55 years or less were reviewed. Immunohistochemical slides for MLH1, PMS2, MSH2 and MSH6 were scored. MSI status of all tumours was determined using FSCCP for deletions in BAT26 and NR24 mononucleotide repeats. <h3>Results</h3> Significant loss of staining, complete loss of nuclear staining in 450% but 5100% of nuclei, for one or more MMR proteins was detected in 25 (36.2%) cases. Six (8.7%) cases had 100% loss for one or more MMR proteins and all (100%) were MSI positive. BAT26 and NR24 deletions were detected in three additional cases that had only 50–80% loss by IHC, therefore 33.3% of cases would have been missed by MMR IHC. <h3>Conclusion</h3> Screening for HNPCC by IHC alone will lead to interpretation difficulties often requiring MSI testing for confirmation. In this study the sensitivity of MSI was higher than IHC, and unlike MMR IHC, MSI testing interpretation is non-ambiguous and easy to interpret. Although IHC and MSI are complementary to each other, we recommend MSI molecular testing to be used as the preferable first line screening method of HNPCC. Depending on the availability of resources, IHC can either be performed in parallel with MSI or only on MSI positive cases.