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)

An increased incidence of colorectal cancer has been observed in breast and breast-ovarian cancer syndrome families, including those of Ashkenazi origin. Recently, a germ-line missense mutation in the APC gene, I1307K, was identified that may indirectly cause colorectal cancer in Ashkenazi Jews. To determine whether the excess of colon cancer in some breast-ovarian cancer families is related to the I1307K mutation, we evaluated 264 Ashkenazi Jews from 158 families. Most of these individuals had either a personal or a family history of breast and/or ovarian cancer, and 19.3% (51 of 264) carried one of the recurrent BRCA1 (185delAG or 5382 insC) or BRCA2 (6174delT) mutations. We detected the APC I1307K mutation in 7% (11 of 158) of the Ashkenazi Jewish families and in 4.5% (12 of 264) of the individuals participating in these studies. Of the families studied, 26.6% (42 of 158) had at least one case of colorectal cancer in a first-, second-, or third-degree relative of the proband. Significantly, of the 12 individuals who possessed the I1307K mutation, none was diagnosed with colorectal cancer and none had a known first-, second-, or third-degree relative diagnosed with colon cancer. The results suggest that factors other than the I1307K mutation contribute to the increased incidence of colon cancer in Ashkenazi breast-ovarian cancer families. Our results emphasize that only a subset of Ashkenazi Jewish individuals with a family history of colorectal cancer should be viewed as candidates for genetic susceptibility testing for the I1307K APC mutation.
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PMID:The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. 940 54

Association of breast tumor susceptibility gene products BRCA1 and BRCA2 with the RAD51 recombination protein suggested that cancer could arise through defects in recombination. The identification of NBS1, responsible for Nijmegen breakage syndrome, from the MRE11/RAD50 recombination protein complex also supports this hypothesis. However, our mutation analysis revealed that known members of the RAD52 epistasis group are rarely mutated in human primary cancer. Here we describe the isolation of a novel member of the SNF2 superfamily, characterized with sequence motifs similar to those in DNA and RNA helicases. The gene, designated RAD54B, is significantly homologous to the RAD54 recombination gene. The expression of RAD54B was high in testis and spleen, which are active in meiotic and mitotic recombination. These findings suggest that RAD54B may play an active role in recombination processes in concert with other members of the RAD52 epistasis group. RAD54B maps to human chromosome 8q21.3-q22 in a region associated with cancer-related chromosomal abnormalities. Homozygous mutations at highly conserved positions of RAD54B were observed in human primary lymphoma and colon cancer. These findings suggest that some cancers arise through alterations of the RAD54B function.
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PMID:Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer. 1036 64

We have investigated frameshift mutations in exonic repeats in the ATR, BRCA1, BRCA2, PTCH, CTCF, Cx26, NuMa and TGFbetaRII genes, using human tumor samples from stomach, esophagus, breast and skin and melanoma, as well as colon cancer and endometrial cancer cell lines (125 samples in total). We developed a sensitive method to detect mutations in the repeats, using the introduction of an artificial restriction site into a repeat. The method detects a single mutant among 10(3) normal genes. Thus, an alteration in a repeated sequence can be detected unambiguously. The (A)(8) repeat of BRCA2 was found mutated in only two of five colon cell lines with microsatellite instability (MI(+)). The ATR gene has an (A)(10) repeat which was altered in two of three MI(+) stomach cancer samples and one of three MI(+) endometrial cell lines. The TGFbetaRII gene [with an (A)(10) repeat] had the maximal frequency of mutations: 10 out of 13 MI(+) samples. At least one sample from all types of cancers, except melanomas, was positive for TGFbetaRII gene mutations. No mutations were found in repeats in the BRCA1, PTCH, CTCF, NuMA and Cx26 genes in any types of tumors examined. In conclusion, our study indicates that repeats were altered only in MI(+) cells and that the mutation frequencies in the genes studied differ among tumor types. Based on these results, we discuss meaningful and meaningless alterations in exonic repeats.
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PMID:A novel sensitive method to detect frameshift mutations in exonic repeat sequences of cancer-related genes. 1054 25

The human Rad51 gene, HsRAD51, is a homolog of RecA of Escherichia coli and functions in recombination and DNA repair. BRCA1 and BRCA2 proteins form a complex with Rad51, and these genes are thought to participate in a common DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair. Additionally, we have shown that the pattern of northern blot analysis of the RadS gene is closely similar to those of the BRCA1 and BRCA2 genes. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancer. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. In both patients, blood DNAs showed a G-to-A transition in the second nucleotide of codon 150, which results in the substitution of glutamine for arginine. As this alteration was not present in any patients with breast or colon cancer examined, we assume that this missense alteration is likely to be a disease-causing mutation.
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PMID:Identification of Rad51 alteration in patients with bilateral breast cancer. 1080 37

Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.
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PMID:Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells. 1110 14

Inherited predisposition occurs in 5-10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients' age range was 38-90 years (mean 65.8+/-11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%, P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information.
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PMID:The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel. 1120 41

We sought to determine whether rare cancers indicate an increased risk of inherited cancer susceptibility. We ascertained 77 individuals with rare cancers which occur with increased relative risk in carriers of germline BRCA1/BRCA2 (fallopian, young-onset pancreatic) or HNPCC (biliary, small intestinal, urothelial, gallbladder, young-onset pancreatic) mutations. Individuals with two primary neoplasms (7), or with a first- or two second-degree relatives with breast/ovarian cancer were tested for BRCA1/BRCA2 mutations (18); those with two primary HNPCC cancers or one first degree relative with an HNPCC-related cancer were tested for mutations in MLH1/MSH2 (19). Of these 77 individuals with cancer (19 fallopian, 8 gallbladder, 17 biliary, 17 pancreatic, 11 urothelial, 5 small intestinal), 39 (50.6%) had at least one first degree relative with cancer (excluding lung and skin); two conformed to Bethesda HNPCC criteria. No definitely pathogenic germline MLH1 and MSH2 mutations were found in 19 individuals, although 2 MSH2 variants were detected. A family history of breast/ovarian, HNPCC or colon cancer in a first degree relative was found in 40% of fallopian, 20% of biliary, 35% of pancreatic, 27% of urothelial and 20% of small bowel cancer patients. A BRCA1 frameshift mutation was detected in a woman with fallopian (54 y) and breast (39 y) cancers, and a BRCA2 nonsense mutation in a woman with biliary (48 y) and breast (45 y) cancers. This study supports the premise that the occurrence of rare (especially double primary) cancers does indicate an increased cancer susceptibility, although the numbers of cases ascertained were too small to draw firm conclusions.
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PMID:Does the occurrence of certain rare cancers indicate an inherited cancer susceptibility? 1457 63

Major risks conferred by BRCA1 and BRCA2 in women are for cancers of the breast, ovary, fallopian tube, and peritoneum. Male carriers of mutations in BRCA1 or BRCA2 are also susceptible to cancer; however, their risks remain poorly understood and their optimal clinical management has not yet been defined. This article reviews studies that estimate risk associated with mutations in BRCA1 or BRCA2, with a focus on the cancer sites most relevant to men. Male BRCA1 mutation carriers are at increased risk of cancers of the prostate and breast. Evidence supporting increased susceptibility to colon cancer is limited. In contrast to women, who have a greater lifetime risk of cancer with mutations of the BRCA1 gene, BRCA2 is the more important gene for men. The spectrum of cancers is wide for BRCA2 and some studies report that the overall cancer risk for male BRCA2 carriers exceeds the risk for female carriers. In particular, the relative risk to male BRCA2 mutation carriers is high before age 65 years, largely attributable to breast, prostate, and pancreatic cancers. BRCA2 mutation carriers are also at risk of stomach cancer and melanoma (of the skin and eye). Additional research into risks to male BRCA1 or BRCA2 mutation carriers is necessary, specifically to determine the magnitude of excess cancer risk among BRCA2 carriers and to increase our understanding of the basis for the observed site-specificity in cancer development.
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PMID:Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. 1496 99

It is important to evaluate the effects of proposed interventions to reduce the risk of disease among carriers of a highly penetrant mutation, such as the mutations in BRCA1 and BRCA2 for breast and ovarian cancers or in APC and MLH1 or MSH2 for colon cancer. However, some studies that evaluate the effects of interventions designed to reduce risk in mutation carriers may be susceptible to a serious selection bias when they are based in clinics that care for persons at high risk for the disease. A study design in which a large fraction of the case patients were diagnosed before being seen at the clinic and all control subjects are persons previously seen at the clinic can create a false impression of intervention efficacy if, as is likely, mutation carriers seen at the clinic were more likely to receive the intervention than mutation carriers in the general population.
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PMID:Bias in intervention studies that enroll patients from high-risk clinics. 1531 55

A prospective study of psychosocial consequences following predictive testing for inherited mutations in breast/ovarian and colon cancer susceptibility genes BRCA1, BRCA2, MLH1, and MSH2 was performed. Eighty-seven healthy women were tested for known family mutations and self-assessment scales were used to evaluate anxiety, depression and quality of life. Extensive pre- and post-test information was given. Questionnaires were responded before testing and four times after during the following year. A statistically significant decrease in anxiety mean scores over time was observed among the studied participants. The levels of depression in cancer genes carriers decreased over time while, surprisingly the levels in non-carriers increased. Compared to a normative Swedish sample all women tested showed similar levels of anxiety but women tested for breast cancer genes showed statistically lower levels of depression. Vitality dropped initially after disclosure of the testing of colon cancer genes carriers, followed by increasing levels. No change in vitality or in other quality of life parameters was seen in the other groups and the levels were similar to Swedish norm data. Most tested individuals were satisfied with the testing procedure including genetic counselling and testing and all of them but one would redo the testing. Healthy self-referred women going through predictive breast/ovarian or colon cancer gene testing, including extensive pre- and post-test information and support, in general, will not experience adverse psychological consequences.
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PMID:Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer pre-disposing genes: a 12-month follow-up. 1534 Feb 61


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