Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred.
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Abstract:
A germ-line mutation of hMSH6 (also called GTBP) was found in a hereditary nonpolyposis colorectal cancer (HNPCC)-like patient in whom germ-line mutations of hMSH2, hMSH3, or hMLH1 had not been detected. The patient had rectal cancer and two colon adenomas at 62 years of age and a weak family history of gastrointestinal tumors, indicating atypical HNPCC. Somatic mutations of hMSH6 were observed in three colorectal tumors from the patient, indicating two-hit inactivation. Microsatellite instabilities at mononucleotide repeats were detected in all three tumors. These data suggest that hMSH6 is responsible for tumorigenesis in atypical HNPCC.Keywords:
Lynch Syndrome
Microsatellite Instability
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PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.
MLH1
Microsatellite Instability
Lynch Syndrome
MSH2
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There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.
Microsatellite Instability
Lynch Syndrome
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Colorectal cancer (CRC) is currently a well-known and studied issue in experimental research. Worldwide it is the third most common cancer in men and the second most common cancer in women. 70-80% of cases occur sporadically. Most CRCs develop from adenomas. The transition from normal epithelium to adenoma and finally into carcinoma is associated with acquired molecular events. In 5-10 % of cases, CRC develops from germline mutations in cancer-predisposing genes. 15% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members. Genetic alterations in cancer-related genes represent prognostic and predictive CRC biomarkers. Genetic testing of individuals with newly diagnosed CRC as well as of asymptomatic relatives can lead to improved outcomes for the patient and at-risk family members. Discovery of circulating cell-free tumor DNA (ctDNA) promises an improvement of the CRC diagnostics. ctDNA shares common genetic alterations with the primary tumor so it allows non-invasive monitoring of the disease over time. This review is focused on the principal molecular biomarkers associated with CRC and on the key characteristics of initiation and progression of CRC including chromosomal instability, microsatellite instability and signaling pathways where this deregulation leads to tumorigenesis.
Microsatellite Instability
Chromosome instability
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Microsatellite Instability
Lynch Syndrome
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BACKGROUND Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI + tumours. RESULTS A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI + tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI + tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.
Microsatellite Instability
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Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM
Microsatellite Instability
Penetrance
Lynch Syndrome
Surgical oncology
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The term Hereditary Nonpolyposis Colorectal Cancer, or HNPCC, has been less used for naming the classical autosomal dominantly inherited susceptibility to cancer [1]. As this susceptibility applies to tumors from different primary sites other than but including colorectal cancer (CRC), the term Lynch Syndrome (LS) is a less restrictive name. Lynch Syndrome is characterized by an autosomal dominantly inherited susceptibility to cancer, caused by inherited germline mutations in the mismatch repair (MMR) genes. It is characterized by early age of onset, predilection to the proximal colon, multiple primary CRCs, and extracolonic tumors, particularly endometrium carcinoma (EC) [2,3].
To establish a profile of the disease, a better definition of the spectrum of related tumors has been a constant concern [4,5]. It is therefore expected to find heterogeneity among the families regarding the susceptibility to develop tumors in different specific sites. The risk of cancer in fact varies among families with LS, although the variation does not necessarily result from genetic heterogeneity. The standards of environmental exposure must contribute to the differential gene expression, justifying at least in part this heterogeneity [6].
LS accounts for 2%–5% of all CRC cases [7]. In fact, it is believed that 20% to 30% of patients with CRC present some type of genetic susceptibility, but without meeting criteria for known typical syndromes. However, new cancer cases in the patient’s family or supplemental information on previously unknown cases can lead to a reclassification that may characterize a typical syndrome. In other situations, despite the lack of clinical criteria for determining an inherited character, molecular inquiry can define the diagnosis of inherited syndrome. For these reasons, even in the absence of typical clinical characterization, criteria must be used to direct the inquiry of an inherited condition.
The spectrum of extracolonic tumors in LS began to be the subject of several publications in which the most common cancers found were those affecting the endometrium, the stomach and the urinary tract [8-14]. Watson and Lynch [6] calculated the frequency of cancer in other specific sites in 1,300 high-risk individuals from 23 families having LS and demonstrated a significant increase of the risk of developing cancer in the stomach (RR:4.1), small bowel (RR:25), kidneys (RR:3.2), ureter (RR:22), and ovary (RR:3.5). The proposed extracolonic cancers associated with LS are endometrium, stomach, ovary, small bowel, ureter, renal pelvis, brain, and hepatobiliary tract. Among these tumors, endometrium, ureter, renal pelvis, and small bowel cancers present the highest relative risk, and are therefore the most specific for LS.
The Amsterdam criteria for clinical diagnosis of LS are: (1) at least three relatives must have histologically verified CRC, endometrium, ureter, renal pelvis, or small bowel cancer; (2) one must be a first-degree relative of the other two; (3) at least two successive generations must be affected; (4) at least one of the relatives with cancer must have received the diagnosis before age 50; and (5) familial adenomatous polyposis must have been excluded. Because there are families with an MMR mutation present exclusively in patients with endometrial cancer without CRC, the requirement of at least one case of CRC was suppressed [15,16].
Patients with LS may also have sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, findings consonant with Torre’s syndrome variant [17,18]. The definition of LS includes a familial clustering of colorectal and/or endometrial cancer and as associated cancers stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract, and skin (sebaceous tumors) tumors [15,19].
As discussed by Vasen [20], since it is known that LS is caused by an mismatch repair gene defect and that the hallmark of the syndrome is microsatellite instability (MSI), more attention should be given to the so-called Bethesda guidelines, which describe almost all clinical conditions in which there is suspicion of LS and in which a search for MSI is indicated, mainly early onset of colorectal adenomas and cancer.
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Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.
Key words:
Hereditary nonpolyposis ; Colorectal neoplasms; Base pair mismatch; Microsatellite instability
Microsatellite Instability
Inherited disease
Lynch Syndrome
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Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2–5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15–70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.
Lynch Syndrome
Microsatellite Instability
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Hereditary non-polyposis colorectal cancer (HNPCC),also called Lynch syndrome,is an autosomal-dominantly inherited disease and is associated with germline mutations in mismatch repair(MMR)genes and microsatellite instability(MSI).HNPCC is the most common form of hereditary colorectal cancer,accounting for 5%-15% of colorectal cancers.HNPCC has characteristic clinicpathological features,such as right-sided predominance,more synchronous or metachronous multiple primary colorectal cancer, young age at diagnosis,and poor histopathological differentiation.Recently,surgery has been the main means of treating HNPCC.However,COX-2 inhibitors may be a new therapeutic approach. Recent molecular biology studies have deepened our understanding of its the biological behavior and therapy.
Microsatellite Instability
Lynch Syndrome
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