Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary non-polyposis colon cancer is caused by mutations in DNA mismatch repair genes. The mutation spectrum in the Israeli population is poorly documented except for the c.1906G>C Ashkenazi founder mutation in the hMSH2 gene. To report our experience in HNPCC screening, the mutations detected and the clinical features among a cohort of Israeli patients. Diagnostic work-up was done in a multi-step process guided by clinical and ethnic information. Tumors of suspected patients were tested for microsatellite instability and immunohistochemistry. Based on tumor analyses, we proceeded to mutation screening by DHPLC followed by sequence analysis and multiplex ligase dependent probe amplification. Ashkenazi Jews were first tested for the c.1906G>C founder mutation. Of the 240 families, 24, including Arabs and Jews from different ethnic origins, were tested positive. All tumors that lost expression of mismatch repair proteins also showed microsatellite instability. There was evidence for involvement of hMSH2 (15) hMLH1 (6) and hMSH6 (3) genes. Mutations were identified in 17/24 (71%) patients: 6 Ashkenazi families harbored the c.1906G>C mutation. Eleven other mutations (2 nonsense, 3 splice site and 6 small deletions) were detected. Three of the mutations are novel. No gross deletions or insertions were detected. This is the first report that characterizes the profile of HNPCC in a cohort of patients in Israel. Tumor testing indicated that the 3 main MMR genes are involved, and that mutation spectrum is broad.
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PMID:Mutation spectrum in HNPCC in the Israeli population. 1838 88

About 90% of gastric cancer (GC) cases appear in a sporadic setting. Nonetheless, in high incidence areas high familial aggregation rates have been recently described. Microsatellite instability (MSI) is thought to be an important molecular phenotype both in sporadic GC and in tumors of the HNPCC spectrum. The aim of this study was to assess the frequency of MSI in GC with familial aggregation. Five quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21 and NR-27) were analyzed in 250 GC patients. Seventy-five patients (30%) had at least one-first-degree family member affected by GC and 63 patients (25.2%) showed MSI. The frequency of MSI was significantly higher in patients with a positive family history of GC (38.7%) compared to patients with other tumor types within the family (15.7%) or with a negative oncological familial history (21.9%, P = 0.004). Within cases with a positive familial oncological history, the MSI frequency in families with GC only was similar to the one observed in families with GC and colon cancer (P = 0.96). Nonetheless, in families with GC and lung cancer, the frequency of MSI was significantly lower (5.6%, P = 0.007). MSI occurs in GCs with familial aggregation. Similar MSI rates have been observed in GC patients with other family members affected by GC or colon cancer. The same does not occur in families with other members affected by lung cancer. Our data seem to suggest that familial aggregation for either GC alone or gastric and colon cancer share common etiological factors in contrast to families with gastric and lung cancers.
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PMID:Evidence of tumor microsatellite instability in gastric cancer with familial aggregation. 1915 22

With improvements to DNA sequencing technologies, including the advent of massively parallel sequencing to perform "deep sequencing" of tissue samples, the ability to determine all of the nucleotide variations in a tumor becomes a possibility. This information will allow us to more fully understand the heterogeneity within each tumor, as well as to identify novel genes involved in cancer development. However, the new challenge that arises will be to interpret the pathogenic significance of each genetic variant. The enormity and complexity of this challenge can be demonstrated by focusing on just the genes involved in the hereditary colon cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis coli (HNPCC). The genes responsible for each disease were identified almost two decades ago -APC for FAP and the MMR genes for HNPCC - and a large number of germline variations have been identified in these genes in hereditary cancer patients. However, relating the effect of an individual genotype to phenotype is not always straightforward. This review focuses on the roles of the APC and MMR genes in tumor development and the work that has been done to relate different variants in each gene to functional aberrations and ultimately tumorigenesis. By considering the work that has already been done on two well-defined diseases with clear genetic associations, one can begin to understand the challenges that lie ahead as new genes and gene mutations are discovered through tumor sequencing.
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PMID:Genotype to phenotype: analyzing the effects of inherited mutations in colorectal cancer families. 1976 28

An 81-year-old woman presented with a chief complaint of swelling of both lower legs. She had a history of surgery for cancers of the stomach, rectum and colon. Among her immediate family members, her son had colon and rectal cancers, and her sister had ovarian cancer. After close examination the patient was diagnosed with small intestine cancer and ascending colon cancer. Gene mutation analyses did not reveal any mutations in DNA mismatch repair genes, but MSH-2 protein expression was lost only in the cancer lesions. Here, we report this rare case of eight metachronous gastrointestinal cancers thought to be HNPCC.
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PMID:Patient with eight metachronous gastrointestinal cancers thought to be hereditary nonpolyposis colorectal cancer (HNPCC). 2011 96

Mutations in the MLH1 and MSH2 genes account for a majority of cases of families with Lynch Syndrome. Germ-line mutations in MSH6, PMS2 and MLH3 are responsible for disease in a minority of cases, usually associated with milder and variable phenotypes. No germ-line mutations in MSH3 have so far been associated with Lynch Syndrome, although it is known that impaired MSH3 activity leads to a partial defect in mismatch repair (MMR), with low levels of microsatellite instability at the loci with dinucleotide repeats in colorectal cancer (CRC), thus suggesting a role for MSH3 in carcinogenesis. To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6. We found 13 mutant alleles, including silent, missense and intronic variants. These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes.
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PMID:Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects. 2112 52

The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair. Microsatellite instability (MSI+ phenotype) induced by germline mutations is characteristic of such tumors and is necessary to assert the diagnosis. The HNPCC syndrome is associated with a significant increased risk of CCR altogether with endometrium, upper urinary tract and small bowel carcinomas as well as ovarian, biliary system and gastric cancers although of lesser extent. It is of importance to diagnose HNPCC syndrome prior to the treatment starts because it may influence patient's (as well as her/his relatives) disease management (type of surgery, surveillance and screening exams). New French recommendations, developed in 2009, about prophylactic colo-rectal and gynecologic surgeries and monitoring update latest ones published on 2004.
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PMID:[HNPCC (hereditary non-polyposis colorectal cancer) or Lynch syndrome: a syndrome related to a failure of DNA repair system]. 2145 14

HNPCC is a diverse disease with significant colorectal and extracolonic malignancy risk. A high index of suspicion is necessary to identify patients and families who potentially have this disease. Patients suspected with Lynch syndrome should be referred for genetic counseling and testing for accurate diagnosis. Timely surveillance and intervention are essential to reduce the incidence and mortality from colorectal cancer. Once cancer is diagnosed, aggressive surgical management is warranted because there is significant metachronous colorectal neoplasia risk for all remaining colorectal mucosa. In medically fit patients, consideration should be given to colectomy for the treatment of colon cancer and proctocolectomy for the treatment of rectal cancer. For patients treated with anything less than total proctocolectomy, annual endoscopic surveillance of the remaining colorectum is mandatory.
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PMID:Surgical management of hereditary nonpolyposis colorectal cancer. 2195 93

A 40-year-old man had undergone right hemicolectomy and sigmoidectomy under the diagnosis of ascending and sigmoid colon cancer and right nephroureterectomy under the diagnosis of right ureteral cancer, in 1997 and in 2002, respectively. In 2007, He visited our hospital with a complaint of bloody stool and hematuria. Colon fiberscopy, ureteropelvicscopy and cystoscopy demonstrated colon cancer, left renal pelvis cancer and bladder cancer, respectively, as diagnosed by biopsies, followed by restative colectomy, left nephroureterectomy and cystectomy. The final histopathological examination showed well differentiated adenocarcinoma (pSM) in the colon, and urothelial carcinoma in the left renal pelvis (pT2) and the bladder (pT1). Since his uncle and elder brother had suffered from stomach cancer and colon cancer, respectively, he was diagnosed with hereditary nonpolyposis colorectal cancer (HNPCC : Lynch syndrome). He has been well doing without recurrence for 3 years after the surgery.
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PMID:[Metachronous urothelial cancer in bilateral upper urinary tracts and bladder associated with hereditary nonpolyposis colorectal cancer]. 2208 54

Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC) is an inherited disease with variable phenotype causing the development of colon cancer and other malignancies. The basis of the disease is believed to be the mismatch repair gene mutations. Genetic screening has been performed among the patients who have undergone surgery for colon cancer at the University of Debrecen, Department of Surgery. Tumor samples of the screened patients were submitted to immunohistochemistry on hMLH1, hMSH2 and hMSH6 genes, microsatellite instability testing, followed by sequencing and multiple ligation dependent probe amplification. Three families were identified with the missense mutation c.143A>C (p.Q48P) of hMLH1 gene. In one of the families a segregation analysis of this particular variant was also accomplished. The segregation analysis revealed a clear correlation between the tumor cases and the occurrence of this mutation. However, none of the analyzed 100 healthy controls demonstrated the same aberration. There is only one published evidence in the literature about the presence of this rare variant in any population. The Gln to Pro switch in the ATPase domain, a conservative region of the hMLH1 gene, creates significant changes in the protein structure. These results indicate that this mutation is the abnormality responsible for the patients' phenotype and it is feasible that this particular aberration occurs more frequently among Hungarian Lynch syndrome patients.
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PMID:Q48P mutation in the hMLH1 gene associated with Lynch syndrome in three Hungarian families. 2239 73

INTRODUCTION: Lynch syndrome was first described in the 1950s however until recently it was rarely included in medical school curricula. As a result, many practicing physicians have limited exposure, potentially contributing to significant under diagnosis. As identification of Lynch syndrome prior to malignancy allows for intensified screening, prophylactic surgery and improved patient outcomes, all physicians should be aware of the characteristics of affected families. We aim to determine the overall level of awareness of Lynch syndrome among medical students at an American medical school. METHODS: A voluntary and anonymous questionnaire was delivered to students at an American medical school. The survey instrument assessed the respondent's perceived knowledge regarding the genetics and recommended screening for carriers of Lynch syndrome mutations. RESULTS: The questionnaire was distributed to the entire student body (405 students) with a response rate of 50%. Fifty-nine percent of students reported that they had learned about Lynch syndrome; 27% of first year students, 44% of second year students; 90% of third year students and 100% of fourth year students. Of the students familiar with Lynch syndrome, the reported knowledge of the underlying genetics was 46%, available genetic screening, 18%, criteria used to screen for the syndrome, 24%, recommendations for colon screening, 31% and recommendations for endometrial cancer screening, 17%. CONCLUSION: The majority of medical students surveyed had been exposed to Lynch syndrome and awareness increased over each year of education. Significantly more students were aware of recommendations for colon cancer screening than endometrial cancer screening (32% versus 17%, p = 0.01). Studies of the natural history of Lynch syndrome indicate that affected women are more likely to present with endometrial cancer than colon cancer and while there are no prospective data proving the efficacy of endometrial cancer screening in this high-risk population, the endometrium is easily accessible and can be sampled using simple office techniques. In addition, prophylactic hysterectomy and bilateral salpingo-oophorectomy are reasonable risk reducing interventions for the prevention of both uterine and ovarian cancer. Our findings suggest that increased emphasis must be placed on teaching the gynecologic manifestations of Lynch Syndrome in order to avoid the misconception that it is simply a colon cancer syndrome.
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PMID:Lynch Syndrome: Awareness among Medical Students at a United States Medical School. 2331 29


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