Hereditary Nonpolyposis Cancer Research Articles

Lynch Syndrome – An Overview of the Worldwide Management of This Silent Killer Within Our Genes

"Lynch syndrome, also known as hereditary non-polyposis cancer syndrome, represents the most common autosomal dominant genetic predisposition for the early onset development of several malignancies. Nearly three decades ago, the discovery of microsatellite instability, a distinctive feature of pathogenic variants within genes encoding mismatch repair proteins, marked a significant leap forward in understanding cancer biology and the underlying spectrum of cancers triggered by these mutations – typical of Lynch syndrome. In recent years, a new treatment paradigm, using immune checkpoint inhibitors, as well as preventive measures has drastically improved the survival rates. Identifying individuals with an inherent predisposition to cancer, through diagnostic protocols followed by personalized screening and treatment algorithms, holds the potential to mitigate premature cancer-related fatalities as well as preventable mortality. It is estimated that only a limited number of patients have been diagnosed, underscoring the importance of implementing specific screening programs for early detection of malignancies to which these patients are susceptible. This article aims to underline the importance of a national protocol tailored to guide a Western-inspired practice for Lynch syndrome patient management, the main aim of the Romanian Society for Lynch Syndrome, by providing an overview of similar initiatives throughout the world."

BRAF mutation: Current and future clinical pathological applications in colorectal carcinoma.

The aims are to review the relevance of the BRAF mutations in the clinical settings of colorectal carcinoma. All the literature concerning BRAF mutations and colorectal carcinoma published in PubMed from 2010 to 2018 was reviewed. Multiple variants of BRAF mutations exist in colorectal cancer, the most common type being V600E. The mutation is found in 5 to 15% of colorectal carcinomas and is less common in Asian populations. BRAF mutations are linked with older age, female gender, cigarette smoking and are more common in the right (proximal) portion of the large intestine. BRAF mutations are associated with carcinomas of high histological grade and advanced cancer stages. Often BRAF mutated carcinomas demonstrate adverse histological features such as lymphovascular invasion, perineural invasion, tumour budding and lymph node metastases. BRAF mutations are found in serrated polyposis syndrome and have a negative correlation with hereditary nonpolyposis colorectal cancer (HNPCC). An array of methods of detection of BRAF mutation in colorectal carcinoma are available, such as immunohistochemistry and next generation sequencing, etc. Combinatorial approaches involving anti-BRAF therapies targeting both MAPK signalling as well as the PI3K/mTOR pathway could be a new approach for treatment of metastatic colorectal carcinoma. To conclude, BRAF mutation is important in the pathogenesis of colorectal cancer. Further research on the detection method as well as its role in target therapy will help to improve the management of patients with colorectal cancer.

Current status of hereditary gastrointestinal neoplasms

Gastric cancer and colorectal cancer are two common malignant tumors in digestive tract. 1% to 3% of gastric cancer and 5% to 15% of colorectal cancer are definitely hereditary cancer caused by germline gene mutation. Hereditary gastric cancer includes hereditary diffuse gastric cancer(HDGC) and hereditary intestinal gastric cancer (HIGC). CDH1 gene mutation is the main reason to cause HDGC, so the first degree and the second degree family members of HDGC patients are recommended to receive CDH1 mutation detection, endoscopic examination every year and undergo preventive total gastrectomy. Hereditary colorectal cancer includes hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome) and familial adenomatous polyposis (FAP). Germline MMR gene mutation detection is the golden standard of the diagnosis of Lynch syndrome. Family members of Lynch syndrome patients are recommended to receive endoscopic examination every year and undergo standard cancer radical operation or total colorectal resection based on individual conditions. FAP is caused by APC gene mutation, so FAP patients are recommended to receive endoscopic examination once or twice every year through their lifetime, while a lot of adenoma occur, resection should be considered. The promotion key of hereditary gastrointestinal neoplasms research is to follow the standard diagnosis and treatment guideline for hereditary gastrointestinal neoplasms and build the clinical and gene information bank of hereditary gastrointestinal neoplasms. The second generation sequencing technique provides favorable research stools in elucidating pathogenesis mechanism of hereditary gastrointestinal neoplasms.

Denaturing high performance liquid chromatography (DHPLC) in detection of microsatellite instability

Background: Microsatellite instability (MSI) is a phenomenon characterized by small deletions or insertions within short tandem repeats in tumour DNA compared to matching normal DNA. MSI analysis is becoming more and more important for detection of hereditary non-polyposis colorectal cancer as well as for sporadic primary colorectal tumours with MSI high phenotype. Use of five quasimonomorphic mononucleotide markers eliminates ultimate need for analysis of germline DNA corresponding to tumour DNA. Here we discuss our method for MSI analysis using denaturating high performance liquid chromatography (DHPLC) in combination with quasimonomorphic mononucleotide microsatellite markers in comparison with previously used methods. The method is high-throughput, accurate, quick and cost-effective and suitable for large-scale studies as well as for daily use with smaller numbers of samples.

Genetic Screening in Lynch Syndrome: Health-Risk Behaviors

This literature review examines health-risk behaviors associated with genetic screening in Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) [1]. There are minimal studies focusing on whether information awareness and health behaviors in high-risk mutation carrier’s impact prevention and management associated with genetic screening. This examination of high-risk mutation carriers of Lynch syndrome and health-risk behaviors associated with genetic screening, suggest that information seeking with perceived risk impact prevention and management reduces psychological distress and the effects of receiving information pertaining to cancer [2,3]. Additionally, family-based and professional information is the most effective and natural way of transmitting genetic information [2,4]. Future research will benefit from exploring the psychological impact during the cancer screening process which could provide screening behavioral tools for optimal cancer outcomes.

Cutaneous manifestation of gastrointestinal disease.

The gastrointestinal (GI) and cutaneous systems are closely linked in origin. Skin manifestations are frequently seen as a part of different GI syndromes. Gastroenterologists play an important role in recognizing the symptoms, patient workup and arriving at appropriate diagnoses, often in consultation with dermatologists. This review discusses the diseases with both cutaneous and intestinal involvement. Hereditary polyposis GI cancers, hereditary nonpolyposis colorectal cancers (CRCs), hamartomatous disorders, and inflammatory bowel disease (IBD) are reviewed with emphasis on the genetic basis, diagnostic, histologic findings, screening modalities, and therapeutic options.

Total colectomy for cancer: Analysis of factors linked to patients' age

Total colectomy (TC) is a valid option for cancer treatment in selected cases. Emergency presentation, association to familial adenomatous polyposis (FAP) or intestinal bowel disease (IBD), hereditary non-polyposis cancer (HNPCC), and synchronous tumors are the common indications to TC for cancer. Despite potential high morbidity and mortality rates for worse general health conditions of the advanced age it has even suggested for elderly patients.We reviewed our experience to analyze the current role of TC comparing different results between young and elderly patients.During the period 1990–2012, 76 patients were operated on TC for cancer. Patients were divided in two groups according to the age [<65 – group A (young) and >65 years old – group B (elderly)] and were compared their systemic and surgical complication, considering the presence of comorbidities, ASA score, lifestyle habits, elective or emergency presentation.Morbidity rate was 7.7% and 38.8% in young and elderly patients respectively.21 systemic complications (3 in group A and 18 in group B) occurred in 17 patients (22.36%) (with the coexistence of two complications in 4 patients belonging to the group B. There were 6 surgical complications (7.9%) (3 in group A and 3 in group B): anastomotic leakage 3, major wound infections 2, postoperative bleeding 1; no intra-abdominal abscess were observed. In 2 cases (2.6%) (1 anastomotic leak and 1 intra-abdominal postoperative hemorrhage) was needed a reoperation.We observed only 2 deaths in the elderly.High ASA score and emergency were associated with worst results. Systemic complications were more frequent in elderly patients cause of significant comorbidities, while the incidence of surgical complications was similar and according to literature.Besides the classic indications, it is a viable surgical option also in cancer associated with complicated diverticulitis. Our data show that TC is a safe and effective procedure providing good results even in elderly patients, when combined with a careful preoperative evaluation and age is not an absolute controindication to this procedure.

Germline mutation analysis, microsatellite instability and clinical pathology in Hazakh in China hereditary nonpolyposis colorectal cancer pedigree

Objective To study the significance of mismatch repair (MMR) gene and microsatellite instability (MSI) in Hazakh in China hereditary nonpolyposis colorectal cancer (HNPCC) pedigree.Methods The tumor tissues and normal intestine mucosa of the 105 members of this family were immunohistochemically examined for hMLH1 and hMSH2.The mutation of BAT25,BAT26,D2S123,D5S346 and D17S250 were analyzed with polymerase chain reaction-single-stmded conformation polymorphism (PCR-SSCP) in tissue paraffin imbedding in all cases of the family.Results MSI-positive rate of 17tumor in HNPCC families group was 100 ％,in which there are 16 patients (94.1％) with high frequency microsatellite instability (MSI-H),1 patients with low frequency microsatellite instability (MSI-L)(5.9％).The negative expression of hMLH1 or hMSH2 rate of 17 tumor in HNPCC families group was 100％.There are 44 patients (50.0％) in the other 88 members of the HNPCC family with MSI-H.There are 40 patients with hMLH1 or hMSH2 MMR protein expression absence in the 44 patients with MSI-H.Conclusion HNPCC patients with MSI-H and hMLH1 or hMSH2 MMR protein expression absence have a better consistency with earlier age of onset,right colon cancer incidence and the occurrence of poorly differentiated carcinoma. Key words: Hereditary nonpolyposis colorectal cancer; Microsatellite instability; Mismatch repair gene; Hazakh

Retroperitoneal undifferentiated pleomorphic sarcoma having microsatellite instability associated with Muir‐Torre syndrome: case report and review of literature

Muir-Torre syndrome represents a rare autosomal dominant familial cancer predisposition disorder defined by the occurrence of cutaneous sebaceous tumors and an internal malignancy, most commonly gastrointestinal carcinoma. Most examples of hereditary non-polyposis cancer syndrome (Lynch syndrome), including the Muir-Torre syndrome, are associated with microsatellite instability (MSI) and germline mutations in mismatch repair genes-most commonly MLH1 or MSH2. We present a 58-year-old man with Muir-Torre syndrome and a large retroperitoneal mass (14.3 cm in greatest dimension) encompassing the left adrenal gland. Sections showed a cellular malignant tumor composed of spindle cells with a high mitotic index and lacking morphologic evidence of adipocytic differentiation. It was weakly reactive for smooth muscle actin (SMA) and negative for desmin, CD117, CD31, CD34, S100 protein and pan-cytokeratin. Further immunohistochemical analysis revealed intact expression of MLH1 but loss of MSH2 in tumor nuclei. Compared to non-neoplastic tissue, the tumor showed MSI in five of seven dinucleotide markers. Fluorescence in situ hybridization (FISH) failed to reveal 12q15 amplification, effectively excluding dedifferentiated liposarcoma as a diagnostic consideration. This is a rare case of a patient with Muir-Torre syndrome who developed a related high-grade undifferentiated pleomorphic sarcoma as the associated internal malignancy.

Molecular biology and clinical features of hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disease associated with germ-line mutations in mismatch repair genes and microsatellite instability. This article reviews the molecular biology and clinical pathology of HNPCC.

Familial aspects of colorectal cancers in southern littoral of Caspian Sea.

About 50,000 new cancer cases occur annually in Iran, of which gastrointestinal (GI) cancers are the most common. Colorectal cancers (CRC) account for the third and fourth most prevalent cancers amongst Iranian men and women, respectively. Since CRC has some well-known hereditary forms with differences in their prevalence according to regional heterogeneity, we designed a study to assess familial aspects of this cancer in subjects who reside in Mazandaran Province, Iran. We interviewed all CRC patients who attended a private GI clinic during 1999-2007, with histologically confirmed diagnoses of colorectal adenocarcinoma, about their family histories of CRC and age at diagnosis. Pedigrees were drawn up to second-degree relatives. A total of 293 CRC cases enrolled in the study, of which 152 were male and 141 were female. The mean age of patients was 52.6±15.2 years. Of these, 98 patients (33.5%) were under the age of 45. A total of 66 cases (22.5%) had familial histories of CRC, being significantly more prevalent in younger subjects (11.2% vs. 44.9%, P<0.0001). Thirty-two patients (10.9%) fulfilled the criteria for hereditary non-polyposis colon cancer. In addition, right-sided colon cancers were more prevalent in those with positive familial histories (P<0.05). Due to the frequency of early-onset CRC and familial syndromes, a more intense screening protocol for early detection of CRC should be developed for this population.

Colonoscopy Intervals and Lynch Syndrome

A previous, nonrandomized study from Finland showed that among patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome), mortality was

Genetic Risk in Colorectal Cancer: Our Knowledge Base Is Expanding

Well-known inherited syndromes — such as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer (CRC), and MUTYH -associated polyposis — account for about 5% to 6% of CRC cases. An additional 10% to 15% occur in people with family histories of CRC for which a genetic basis is not clearly defined. Recent genome-wide research has focused on mutations that might account for previously unexplained genetic risk or other phenotypic variation in CRC, even though individually their …

Frequency of Endometrial Carcinoma in Patients with Postmenopausal Bleeding

Introduction: Postmenopausal bleeding (PMB) is defined as bleeding that occurs after 1 year of amenorrhea in a woman who is not receiving hormone replacement therapy (HRT).1 About 10% of women with postmenopausal bleeding have a primary or secondary malignancy. Common malignancies among them are endometrial cancer (80%), cervical cancer or an ovarian tumour.1 Endometrial cancer is the second most common cancer associated with hereditary non-polyposis colorectal cancer.2 Ninety percent of patients have benign causes. Objective: The objective of this study was to determine the frequency of endometrial carcinoma in patients with post-menopausal bleeding. Study Design: Descriptive case series study. Setting: Department of obstetrics and gynaecology, Lady Willingdon, Lahore. Duration of Study: This study was conducted over a period of six months from 1st January 2009 to 30th June 2009. Subjects and Methods: 50 cases with postmenopausal bleeding. Results: During the period of this study a total number of 50 consecutive patients who met inclusion criteria were enrolled in the study. Ages of the patients who presented with PMB ranged between 48 years and 80 years with a mean age of 59 years. Malignancy was found in 18 out of 50 cases (36%).Cases with endometrial CA were 14 out of 50 cases (28%) and CA cervix constituted 4 out of 50 cases (8%). Benign pathology was more frequent (64%). 13 of 50 cases (26%) had hyperplasia out of which 1 case (2%) was of atypical hyperplasia. Endometrial polyp was found in 4 of 50 cases (8%). 3 of 50 cases (6%) had chronic endometritis. 5 of 50 cases (10%) had chronic cervicitis. While 7 cases (14%) had postmenopausal bleeding due to decubitus ulcer of uterovaginal prolapse. Among malignancies (36%), endometrial cancer is the most frequent malignancy in women with postmenopausal bleeding with mean age of 65years. Conclusion: In this study it was concluded that the majority of cases of PMB would be expected to be suffering from benign problems. The main aim of evaluation of cases of PMB is to exclude or identify endometrial or cervical carcinoma and atypical endometrial hyperplasia. Key Words: Postmenopausal bleeding, menopause, endometrial carcinoma.

Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome

High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.

Cancer risk prediction for mismatch repair germline mutation in Chinese hereditary non-polyposis colorectal cancer pedigree

Objective To investigate the cancer risk prediction by means of mismatch repair (MMR) germline mutation test in Chinese hereditary non-polyposis colorectal cancer (HNPCC) pedigree.Methods A detail pedigree analysis about the onset of cancer was carried out in 316 subjects from 43 Chinese HNPCC families,and the results were statistically analyzed.Results ①Two hundred and sixty-three subjects aged above 20 years were identified as mutation.Among whom,144 were mutation carriers and 119 were non-mutation carriers.The prevalence of tumors referred to HNPCC was 9.03%(85/144) in mutation carries and 2.52% (3/119) in non-mutation carriers with significant difference (P＜0.01).②Nevertheless,male subjects had a higher colorectal cancer risk than female subjects in 144 mutation carriers aged above 20 years with significant difference [72.00%(54/75) vs.44.93%(31/69),χ~2=10.89,P＜0.01].③The risk for HNPCC associated tumor was increasing with aging.Conclusions In the HNPCC families,the mutation carriers are the high risk members for cancers related to HNPCC,which can be predicted by means of MMR germline mutation test. Key words: Colorectal neoplasms; hereditary nonpolyposis; DNA mismatch repair; Risk factors

Identification and Management of Lynch Syndrome

The Lynch syndrome, (also as hereditary nonpolyposis colorectal cancer) is an autosomal dominant disease, caused by germline mutations in four mismatch repair (MMR) genes (MSH2, MLH1, PMS2, and MSH6), most notably MLH1 or MSH2, Tumors caused by loss of mismatch repair gene function exhibit frequent errors in microsatellite DNA, short segments of DNA containing 1~6 repeats of nucleotides, and are thus said to exhibit microsatellite instability (MSI). Ninety percent of colon cancers associated with Lynch syndrome show MSI, while only 15% sporadic CRCs have MSI, caused mainly by hypermethylation of MLH1 promoter. Unlike familial adenomatous polyposis, clinical features of the Lynch syndrome are not so unique. However, the Lynch syndrome could be suspected at a relatively early age at onset of CRC, on account of a higher incidence of synchronous and metachronous CRCs, a predilection for the proximal colon, and specific pathologic findings including tumor-infiltrating lymphocytes, signet ring cells, or a strong mucinous component. Although the Lynch syndrome accounts for only 2 to 5% of all colorectal cancer patients, the identification of this syndrome is clinically relevant. Aggressive surveillance including colonoscopy for patients with Lynch syndrome and their relatives could prevent cancer development and reduce mortality. Currently, patients fulfilling the Amsterdam II/Revised Bethesda criteria are suggested to receive MSI and/or IHC analysis of the tumor. Mutation analysis should be offered in those with evidence of MSI or loss of MMR expression.

Revised Bethesda Guidelines vs. MSI Testing for the Detection of HNPCC Mutations

Identification of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers is currently suboptimal, even in cancer patients and their family

Cyclooxgenase-2, β-catenin and matrix metalloproteinase-7 expression and their correlation with invasion/metastasis behaviours of hereditary nonpolyposis colorectal cancer

目的：本研究旨在探讨COX-2、β-cat和MMP-7表达与HNPCC特殊侵袭转移生物学行为间的关系。 方法：应用免疫组化SP法检测HNPCC(n=28)、散发性大肠癌(n=30)和正常大肠黏膜(n=10)中COX-2, β-cat和MMP-7的表达情况。所有标本预先经过hMSH2和hMLH1免疫组化染色筛查，并结合其临床病理特点进行回顾性分析。 结果：在HNPCC组和散发性大肠癌组中COX-2、异位β-cat和MMP-7的表达差异显著(χ^2=14.8352, P=0.0001; χ^2=5.6425, P=0.0175; χ^2=10.6454, P=0.0011)。两组异位β-cat和MMP-7的阳性率与大肠癌的侵袭深度和淋巴结转移密切相关(P=0.0127, 0.0001; P=0.0227, 0.0261)，而与性别、肿瘤的大小和部位无关。COX-2在HNPCC组中与肿瘤侵袭深度相关(P=0.0166)，与淋巴结转移无关；散发性大肠癌组中与肿瘤侵袭深度和淋巴结转移均无关。两组中COX-2、异位β-cat和MMP-7三者阳性表达呈正相关(COX-2与异位β-cat: r=0.417, P=0.011, r=0.504, P=0.006; 异位β-cat与MMP-7: r=0.396, P=0.027, r=0.429, P=0.021; COX-2与MMP-7: r=0.315, P=0.028, r=0.429, P=0.021)。 结论：COX-2、异位β-cat和MMP-7在HNPCC、散发性大肠癌和正常黏膜中的阳性表达率差异显著，这可能是HNPCC相对于散发性大肠癌侵袭弱、转移少的原因之一。

Screening the hereditary nonpolyposis colorectal cancer by revised Bethesda guideline: a cohort study of 110 cases

To study the value of screening hereditary nonpolyposis colorectal cancer (HNPCC) by the revised Bethesda guideline and the rate of HNPCC in colorectal cancer (CRC). Tumor tissues and normal colorectal mucous membrane tissues were collected from 110 successive cases with CRC, 66 males and 42 females, aged 60.8 (26 - 94). Fluorescence multiplex polymerase chain reaction was used to detect the microsatellite instability (MSI). The peripheral blood samples were collected from the patients with MSI, genomic DNA was extracted, and PCR and DNA sequencing were used to detect the germline mutations of hMSH2, hMSH6, and hMLH1. Twenty-three out of the 110 patients (20.9%), 12 males and 22 females, aged 57 (47 - 94), had MSI. Seven germline mutations were found in these 23 MSI patients, accounting for 6.4% among the 110 CRC patients, including 3 cases of hMSH2 mutation, 3 cases of hMSH6 mutation, and 1 case of mutation of hMLH1. Screened by revised Bethesda guideline, the rate of MSI CRC is 20.9% and the rate of HNPCC is 6.4%. The missence germline mutations of hMSH2 and hMSH6 are more common in the Chinese patients with CRC.