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M Ilyas

Publications and source records attributed to M Ilyas.

At least 19 recordsLinked to original sources
PubMed1997

Molecular genetics of colon cancer.

Colorectal cancer remains a major health problem. Few therapies are effective apart from surgery, and survival has increased little in recent years. This is despite the fact that screening by colonoscopy can potentially remove nearly all colorectal tumours before they become malignant. Molecular genetics has identified some inherited mutations (such as at APC and the mismatch repair loci) that predispose to colon cancer and some somatic mutations (such as at APC and p53) that cause sporadic colon tumours. We review the likely role of these and other genes in colorectal tumorigenesis. We also highlight areas of relative ignorance in colon cancer and emphasise that many important genes, especially those that cause invasion and metastasis, remain to be identified. Colorectal cancer is, however, a well characterised tumour, as regards both its natural history and its histopathology; there are consequently good prospects for advances in colon cancer genetics, with probable benefits for its treatment. We anticipate: (a) that new genes predisposing to colon tumours, including those conferring relatively minor risks, will be characterised; (b) genes and proteins important in invasion and metastasis will be identified; (c) the network of protein interactions in which molecules such as APC are involved will be elucidated; (d) large-scale studies of somatic mutations in tumours will provide accurate predictions of prognosis and suggest optimal therapeutic regimens; and (e) new potential targets for therapy will be identified. Whilst molecular genetics is by no means sufficient for progress in preventing and treating colon cancer, it is a necessary and central part of such advances.

Adenoma↗
PubMed1997

Allele loss, replication errors and loss of expression of E-cadherin in colorectal cancers.

BACKGROUND: Loss of E-cadherin expression has been implicated in the development of invasive characteristics in colorectal carcinomas. Failure to express E-cadherin may result from mutations of the E-cadherin gene (HSECAD). AIMS: To examine the correlation between E-cadherin expression and genetic changes at HSECAD; and to examine differences in E-cadherin expression and genetic changes at HSECAD between three different groups of colorectal cancer--replication error positive (RER+) sporadic cancers, RER--sporadic cancers and ulcerative colitis associated cancers. SUBJECTS AND METHODS: Sixty eight colorectal cancers (22 RER+ sporadic cancers, 32 RER- sporadic cancers and 14 ulcerative colitis associated cancers) were studied using immunohistochemistry and for allele loss at the HSECAD locus. Exon 16 of HSECAD contains several mononucleotide repeat tracts which are very similar to microsatellite repeats and which may be susceptible to replication errors (manifest as new alleles). All cases were also examined for new alleles in exon 16. RESULTS: Absent or decreased E-cadherin protein expression was found in 27 (38%) of 68 colorectal cancers and the pattern of expression did not differ significantly among the three tumour groups. Allele loss occurred at HSECAD in four (10%) of 40 informative cancers and there were no differences between the three subgroups. New alleles at exon 16 were detected in three (14%) of 22 RER+ tumours; no new alleles were detected in RER- or ulcerative colitis associated cancers. Overall, there was no correlation between allelic loss or exon 16 replication errors and immunohistochemical E-cadherin expression. CONCLUSIONS: (1) Loss of E-cadherin expression probably does not occur as a result of mutation at the HSECAD locus in colorectal cancers. (2) There is no difference in the frequency of loss of heterozygosity at HSECAD among RER+, RER- and ulcerative colitis associated colorectal cancers.

Alleles↗
PubMed1997

Tumour recurrence is associated with Jass grouping but not with differences in E-cadherin expression in moderately differentiated Dukes' B colorectal cancers.

AIMS: To assess whether immunohistochemical expression of the putative invasion suppressor, E-cadherin, is associated with tumour recurrence in colorectal cancer, independent of Dukes' stage and degree of differentiation, and thus to determine whether measurement of E-cadherin is clinically useful. METHODS: 90 moderately differentiated Dukes' B colorectal carcinomas from patients who had been followed up for at least six years were examined. All were from curative resections performed at St Mark's Hospital and the tumours were shown, on histology, to be clear of all resection margins. Tumours were reviewed and additionally classified in accordance with the Jass grouping system. Immunohistochemical analysis of E-cadherin expression was performed for each tumour using the monoclonal antibody HECD 1. RESULTS: The Jass group ranged between I and III and there was a significant association between Jass group and tumour recurrence (p < 0.05). Positive E-cadherin expression was seen in 40/69 (58%) of non-recurrent and 13/21 (62%) recurrent cases respectively. There was no significant difference in E-cadherin expression between the two groups of tumours. CONCLUSIONS: Even when controlled for Dukes' stage and differentiation, the Jass grouping system yields useful prognostic information; E-cadherin, however, does not predict outcome in the important group of moderately differentiated Dukes' B colon cancers, and may be of little independent prognostic value in other colon cancers.

Cadherins↗
PubMed1996

Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability.

Defects in mismatch repair (MMR) can result in the development of a 'mutator phenotype', manifest as an increase in DNA replication errors (RERs). Patients with hereditary non-polyposis colorectal cancer (HNPCC) have germline mutations in MMR genes. These patients develop carcinomas of the colon and other specific sites at a significantly earlier age than patients with sporadic carcinomas. RERs are found in the cancers from patients with HNPCC and have been demonstrated in 10-20 per cent of sporadic colorectal cancers (CRCs). Loss of MMR may simply accelerate tumour development, but it is also possible that these tumours follow a different carcinogenetic pathway from tumours with intact MMR. In particular, it has been suggested that p53 mutations occur less often in RER-positive (RER+) sporadic colorectal cancers. In this study, the clinico-pathological features and frequency of p53 overexpression in 17 left-sided RER+ CRCs were compared with 35 left-sided RER- CRCs. No differences were found in the age and tumour stage at presentation, mucinous differentiation, or Jass prognostic grouping between these two types of CRC. Thirteen out of 17 (76 per cent) RER+ and 19/35 (54 per cent) RER- tumours showed overexpression of p53, a non-significant difference (chi 2 test). Although some previous studies have suggested differences in the clinico-pathological features and p53 expression of RER+ and RER- right-sided CRCs, our results show that these differences do not exist in left-sided cancers.

Aged↗
PubMed1996

Changes in Bcl-2 and p53 expression in recurrent B-cell lymphomas.

The aim of this study was to investigate the changes involved in the evolution of nine cases of recurrent B-cell lymphomas. Using the polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded tissue from both the primary and the recurrent lymphoma of each case, monoclonality was demonstrated in every tumour. In all nine cases, the recurrent lymphoma was shown to belong to the same clone as the primary lymphoma. Eight of these cases were then investigated by immunohistochemistry for changes in Bcl-2 and p53 expression. Five out of eight of the primary lymphomas showed Bcl-2 overexpression. Two of the three cases initially negative for Bcl-2 expression became positive in the recurrence. One out of eight of the primary lymphomas was positive for p53 expression. Of the seven negative cases, one became positive for p53 expression in the recurrence. Both of the p53-positive cases showed high-grade histology. This study shows that Bcl-2 overexpression is probably an important early event in the development of B-cell lymphomas, although it may occur as a post-neoplastic event. p53 mutation is probably more important as a late event and may be associated with high-grade transformation.

Gene Expression Regulation, Neoplastic↗
PubMed1996

Serious infections due to penicillin-resistant Streptococcus peneumoniae in two children with nephrotic syndrome.

Children with nephrotic syndrome are susceptible to the development of invasive bacterial infections, particularly those caused by Streptococcus peneumoniae. Recently, penicillin-resistant pneumococcal infections in children have occurred in increased frequency in some regions. We have seen two children with nephrotic syndrome who developed penicillin-resistant pneumococcal bacteremia and/or peritonitis. A change in the initial therapy from penicillin in the usual dose in these patients must be considered.

Female↗
PubMed1996

Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability.

Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Genetic pathways in colorectal cancer.

The model of colorectal tumorigenesis put forward by Fearon and Vogelstein has had great influence on molecular oncology. They proposed that a series of mutations occur in the progression from normal cells to colorectal cancer and that these mutations are associated with the histological features of such tumours. Several postulates of the model appear to be correct, particularly its emphasis on the stepwise accumulation of genetic changes and the inclusion of mutations at the adenomatous polyposis coli (APC) and TP53 loci. Since the publication of the original model, however, mutations at other loci have been identified which may be alternatives or additions. There is also evidence to suggest that some colorectal cancers develop along a different genetic pathway. In this review, we discuss how tumour development can occur as Darwinian evolution through selection of advantageous somatic mutations. The non-random nature of mutation selection gives rise to genetic pathways of tumorigenesis. In addition, we consider the Fearon and Vogelstein model, its shortcomings and possible additions to it. The evidence suggests that not all colorectal cancers follow the same genetic pathway during carcinogenesis.

Carcinoma↗
PubMed1996

Late stenosis of an aortorenal bypass graft fashioned from pericardium.

Renal artery stenosis (RAS), especially secondary to fibromuscular dysplasia, is a curable cause of hypertension in children. Although aortorenal bypass was the preferred treatment for this disease twenty years ago, newer techniques are available. We report a 27-year-old patient who, at 7 years of age, had severe hypertension secondary to RAS in a solitary kidney. Aortorenal bypass with an autologous pericardial graft resulted in normal blood pressure for 20 years until the pericardial graft thrombosed. Normal blood pressure has again been achieved following resection of the stenotic renal artery with reanastomosis to the aorta.

Anastomosis, Surgical↗
PubMed1996

Bcl-2 expression in colorectal tumors: evidence of different pathways in sporadic and ulcerative-colitis-associated carcinomas.

Colorectal cancers (CRCs) differ in their age at presentation, distribution, histological features, and prognosis. If tumor biology reflects genetic events, these tumors might be expected to show differences in their genetic pathways. In this study, we investigated the role of Bcl-2 in the development of three different tumor groups. Using markers at eight different microsatellite locl, we characterized one group of 34 left-sided sporadic CRCs as replication error negative (RER-) and another group of 18 left-sided sporadic CRCs as replication error positive (RER+). These tumors, together with a third group of 22 left-sided ulcerative-colitis-associated CRCs (UCACRCs), were then examined by immunohistochemistry for Bcl-2 overexpression. Of 34 of the RER- tumors, 21 (62%) and 10 of 18 (56%) of the RER+ tumors were positive for Bcl-2 overexpression. In contrast, only 5 of 22 (23%) of the UCACRCs showed similar overexpression. Our results show a significantly lower frequency of Bcl-2 overexpression in UCACRCs as compared with sporadic CRCs (P < 0.005) but no difference between sporadic left-sided RER+ and RER- CRCs. These data provide additional evidence that UCACRCs may develop along a pathway that is different from that of sporadic CRCs.

Carcinoma↗
PubMed1996

Radiological manifestations of primary gout.

Gout is an ancient disease not uncommonly seen in radiological practice. Twenty-two patients of suspected gout were examined over a period of 11 years (1984-1995). There were 20 males and 2 females with ages between 35-70 years. First metatarsophalangeal joint was involved in 18 patients. Tophaceous deposits in hands were seen in one, whereas another patient had urate deposit in the lateral condyle of the humerus. One patient had opaque renal stones bilaterally and lucent stones in the right kidney, confirmed by ultrasound, were observed in one case. All of the patients had hyperuricemia. A definite family history was recorded in only three cases. Two patients in the present series were diabetic.

Adult↗
PubMed1995

Non-Hodgkin's lymphoma, coeliac disease, and Epstein-Barr virus: a study of 13 cases of enteropathy-associated T- and B-cell lymphoma.

A group of 166 patients with coeliac disease was followed for a period of up to 25 years. During this time, 17 patients developed intestinal tumours that were diagnosed as lymphoma, of which 15 cases were available for review. Eleven of the lymphomas were of T-cell type (enteropathy-associated T-cell lymphoma, EATL) and two were of B-cell type. Two cases were reclassified as undifferentiated carcinoma. The interval between the diagnosis of enteropathy and the onset of lymphoma varied from less than 2 months in four patients to more than 5 years in seven. Seven of the T-cell and both B-cell lymphomas were investigated for the presence of Epstein-Barr virus (EBV) by in situ hybridization (ISH) using probes against Epstein-Barr virus-encoded RNAs (EBERs) and by immunohistochemistry with EBV-specific monoclonal antibodies. All EATL cases were negative, suggesting that EBV is not an important factor in these cases. In one of the B-cell cases, EBV was detectable by ISH and immunohistochemistry in most tumour cells in the mesenteric lymph nodes, but not in any of the tumour cells in the primary ileal tumour, indicating that in this case EBV infection was a late event in the neoplastic process. These results show that lymphoma may develop any time after the onset of coeliac disease and that in our cases of EATL, EBV was not an important factor. In some cases of EBV-related neoplasia, virus infection may be a late event.

Adult↗
PubMed1995

The use of the polymerase chain reaction in the diagnosis of B-cell lymphomas from formalin-fixed paraffin-embedded tissue.

In this study the use of the polymerase chain reaction (PCR) to detect monoclonality in B-cell lymphoid proliferations in archival formalin-fixed paraffin-embedded tissue was assessed. Using consensus primers against the framework 3 (FR 3) region of the immunoglobulin heavy chain gene (IgH), PCR analysis was performed on 29 low grade B-cell non-Hodgkin's lymphomas. Cases of benign lymphoid hyperplasia served as polyclonal controls. Sequenced cases of acute lymphoblastic leukaemia served as positive controls. In the lymphomas, monoclonality could be demonstrated in 18 of 29 (62%) cases. Only five of 11 (45%) follicle centre cell lymphomas were positive by this method whilst the success rate for the remainder was 13 of 18 (72%). None of the polyclonal controls gave false positive results although occasional non-specific dominant bands were present which disappeared on repeating the experiments. These results show that this method will identify monoclonality in 62% of low grade B-cell non-Hodgkin's lymphomas in archival material. The success rate is increased to 72% if follicle centre cell lymphomas are excluded. Thus, this method is a useful adjunctive test to aid diagnosis in lymphoid infiltrates when standard morphology and immunohistochemistry are equivocal.

Base Sequence↗
PubMed1995

p53 expression in ulcerative colitis: a longitudinal study.

p53 Mutation is a late event in the development of sporadic colorectal carcinoma (CRC). The timing of p53 mutations in the development of ulcerative colitis associated colorectal carcinoma (UCACRC) is, however, less certain and some reports suggest that it may be a relatively early event. This study sought to establish the timing of p53 mutations in neoplasia arising in ulcerative colitis. Blocks of 10 resected colorectal specimens from patients who had had a biopsy positive for dysplasia at least one year prior to resection were retrieved from the archives of St Mark's Hospital. Immunochemistry using the monoclonal antibody DO-7, specific for both mutant and wild type p53, was performed on sections from both the resection specimens and dysplastic biopsy specimens. Seven of the 10 resection specimens were positive for p53. Two of these seven specimens showed p53 overexpression in specimens taken two years before the development of carcinoma or high grade dysplasia. Five of the seven specimens were negative for p53 overexpression between one and four years prior to resection. These results suggest that p53 overexpression is usually a late event in the development of UCACRCs.

Colitis, Ulcerative↗