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Diet, colonic metabolism and colon cancer risk
A520
AGA ABSTRACTS
REARRANGEMENTS OF T-CELL RECEPTOR GENES PRIOR TO IMMUNOGLOBULIN GENES BY H.PYLORI IN MALT LYMPHOMA. K.Okazaki, M.Mnrita, I.Nishimod, Y.Nakazawa, Y.Yokoyaraa, Y. Yamamoto. 1st Dep. of Internal Medicine, Kochi Medical School, Nankoku, Kuehi, 783, Japan In 1983 Isaacson et ai. proposed a distinctive type of B-cell lymphoma arising from mucusa-assoeiated lymphoid tissue (MALT). Recently, there are several papers about eradication of the organism led to a regression of MALT lymphoma. In the past several years, we prospectively observed rearrangements of T-ceU b-receptor (TCRb) and irnmunoglobulin heavy chain (JH) genes in patients who seemed to develop from reactive lympho-reticular hyperplasia (RLH) to low-grade Bcell MALT lymphoma. Materials and method: Clinical samples were prospectively obtained from biopsy specimen at gastroscopy in 5 RLH patients, one of who developed from RLH to MALT lymphoma. Ten pg of DNA from all samples were digested with the restrictive enzymes Barn HI, EcoRI and HindIII, and were separated On 0.8 percent agarose gels for 16-20h at 1V/cm, transferred to nylon membrane, and hybridized w i t h P-32 labelled JH and CTb probes. Filters were then washed extensively at 65"C in 0.5 x SSC, 0.I per cent SDS and the hybridizing bands visualized by autoradiography. Results: Only rearrangements ofT-cell receptor (TCR) were identified in all RLH patients. Both TCR and immunoglnbulin heavy chain gene rearrangements (JH) were identified in patients, who developed from RLH to low-grade B-cell MALT lymphoma. H. pylori was separated from antral biopsied mucosa in all patients. After eradication of H.pylorl, gastroseopie and histological findings showed regression of these gastric lesions, These findings supported that proliferation of low-grade MALT lymphomas depends on an H pylori induced T-cell-mediated stimulation. ref.Okazaki K, et al. Lancet. 343:1636,1994
• hMSH2 GERMLINE MUTATIONS SCREENING IN 50 FAMILIAL CANCER AGREGATIONS. S Olschwang**, P Lat~rent-Puig*, C Boisson°, B Vogelstein#, G Thomas *°. Institut Curie, *laboratoire de G6n6tique des Tumeurs CJF9201, °unit6 de G6ndtique, 26 rue d'Ulm, 75005 Paris; #Johns Hopkins Hospital, Baltimore USA Hereditary Non PoiYposis Colorectal Cancer .is a common autosomal dominant condition predisposing to cancer. It is characterized by the development of tumors of colon, endometrium and less frequently other sites. Recently, germline mutations in HNPCC patients were detected in four different DNA-mismatch repair genes, namely hMSH2 (2p16), hMLH1 (3p21), hPMS1 (2q31-33) and hPMS2 (7p22). The spectrum of hMSH2 gene mutations has been examined among a series of French HNPCC families. Patients and Methods: Our study included 50 familial agregations of cancer. They were either colon site-specific (SS-HNPCC, 13), or non site-specific (NSS-HNPCC, 32), or Muir-Torte syndrom (3) or Cowden disease (2). Screening for hMSH2 mutations was performed on genomic DNA from one affected member Of each family using the DGGE technique. Electrophoretic variants were then directly sequenced and all available blood samples from other family 'members were checked for the corresponding mutations. Results: The entire coding sequence and all splicing junctions were screened. Among the 50 independent propositi, 16 rare and 1 frequent electrophoretic variants were found. In 11 cases, the nucleotide variation was predicted to modify the aminoacid sequence : nonsens and frameshift mutations were found in 7 cases. In 4 cases, the variant was expected to lead to an amino-acid substitution. The 6 other electrophoretic variations resulted from 2 silent nucleotide substitutions in exons 2 and 13 respectively. Segregation of the DNA variants was studied in 8 families. In 2 families in which an identical missense mutation had been found, cosegregation of the mutation with the disease did not occur. The prevalence of hMSH2 mutations appears to vary among the different subgroups of familial agregations of cancer : 7 mutations in NSS-HNPCC families (22%), 1 in SS-HNPCC families (8%) and 1 in a Muir-Torre family. Conclusion: hMSH2 germline mutation appears to be preferentially assOciated with non site-specific familial agregations of cancer. Because in most cases the mutation lead to the synthesis of a truncated protein, in absence of a functional test, the causal relationship of the detected DNA variation with the HNPCC disease can be expected; an information that is helpful in genetic diagnosis of at-risk members in affected families.
GASTROENTEROLOGY, Vol. 108, No. 4
DIET, COLONIC METABOLISM AND COLON CANCER RISK. SJD O'Keefe, M Kidd, G Noel, GO Young. Gastrointestinal Clinic, Groote Schuur Hospital, University of Cape Town, South Africa. Epidemiological studies have demonstrated that dietary items such as fibre, fish oils, vitamins C,A and E and minerals calcium and magnesium are associated with low risk whilst animal products (proteins and fats) and excessive calories are associated with higher risk of colon cancer. Recent evidence suggests that colonic flora composition and short chain fatty acid production also affect risk. In eider to investigate the relative importance of these factors in African populations with varying cancer risk, dietary intake, colonic bacterial fermentation in response to a 200g maize-meal, colonic cell differentiation measured by rectal biopsy and staining for K167, p53 and TGFas well as lhr BrDU uptake, and blood tests were performed on 20 healthy volunteers (age > 40 years) from each of the following population groups a) a high risk group consuming a Western type diet: risk 20/100 000, b) a fishing community: risk 5/100 000 and c) a black community consuming a high carbohydrate, low animal protein diet: risk 1.8/100 000. RESULTS confirmed a correlation between all four cell proliferation markers and overall cancer risk within the three populations. However, dietary intakes of fibre, vitamins A and C and calcium and magnesium were all lower in the two low risk populations. Furthermore, group mean total caloric intakes and body mass indices were similar between the three groups. Blood levels demonstrated lower vitamin levels in the two low risk populations whereas omega-3 fatty acids were significantly higher in fishermen (9.5+1.8) and in black subjects (4.3 + 1.1) than in the Westernized group (3.6+0.6), p < 0.05). In contrast omega-6 fatty acids were higher in the Westernized group (42.2 + 3.2 versus 39.1 + 1.1 and 37.4 + 1.7). Breath hydrogen response to the carbohydrate meal was marginally higher in the two low risk groups but breath methane excretion was markedly higher in blacks (37.5+7.8 versus 10.54-1.5 in Westernized group and 14.54-2.4 in fishermen, p < 001). In conclusion, the lower incidence of colon cancer in blacks eeuld be explained by the high carbohydrate diet and greater colonic bacterial methanogenesis, whilst the low rate in fishermen was associated with high omega-3 (fish oil) fatty acids. Our results would support the hypothesis that colonic health is maintained by short chain fatty acid production by colonic bacteria with the removal of excess hydrogen by methanogenie bacteria, and also the antiinflammatory and potential anti-neoplastic effects of butyrate and omega-3 fatty acids. In this study vitamins, minerals and fibre did not appear to affect risk.
DEMONSTRATION OF REMARKABLE REDUCTION 1N "DENOVO" COLON CANCER IN COLONOSCOPY FOLLOW-UP Harvey W. Olsen and William A. Lawrence, Oakland, California We have been able to demonstrate a dramatic reduction in colon cancer in patients who complied with our follow-up guidelines vs those who did not after initial colonoscopy and polypectomy. In our study population of 1441 patients who had polyps we have done follow-up colonoscopy on 371 patients who have more than 3 years follow-up (4-17 years). 176 of these patients had at least one colonoscopy within the first three years of initial exam and have had follow-up thereafter for an average of 6 years. We have 195 patients who for various reasons did not have an interval colonoscopy but whom eventually had a eolonoscopy sometime after three years of foUow-up with an average of 7 years. There was one insitu cancer identified in the follow-up group and there were nine invasive cancers in the group without initial follow up in the first three years. The incidence of cancer was approximately seven times more frequent in the non-compliant group vs those who did appropriate follow-up~ Our study data for follow-up patients is similar to the observations made in the National Polyp Study but also demonstrates the value of fo!lowup colonoscopies and polypectomies as part of the prevention program.
AGA ABSTRACTS
REARRANGEMENTS OF T-CELL RECEPTOR GENES PRIOR TO IMMUNOGLOBULIN GENES BY H.PYLORI IN MALT LYMPHOMA. K.Okazaki, M.Mnrita, I.Nishimod, Y.Nakazawa, Y.Yokoyaraa, Y. Yamamoto. 1st Dep. of Internal Medicine, Kochi Medical School, Nankoku, Kuehi, 783, Japan In 1983 Isaacson et ai. proposed a distinctive type of B-cell lymphoma arising from mucusa-assoeiated lymphoid tissue (MALT). Recently, there are several papers about eradication of the organism led to a regression of MALT lymphoma. In the past several years, we prospectively observed rearrangements of T-ceU b-receptor (TCRb) and irnmunoglobulin heavy chain (JH) genes in patients who seemed to develop from reactive lympho-reticular hyperplasia (RLH) to low-grade Bcell MALT lymphoma. Materials and method: Clinical samples were prospectively obtained from biopsy specimen at gastroscopy in 5 RLH patients, one of who developed from RLH to MALT lymphoma. Ten pg of DNA from all samples were digested with the restrictive enzymes Barn HI, EcoRI and HindIII, and were separated On 0.8 percent agarose gels for 16-20h at 1V/cm, transferred to nylon membrane, and hybridized w i t h P-32 labelled JH and CTb probes. Filters were then washed extensively at 65"C in 0.5 x SSC, 0.I per cent SDS and the hybridizing bands visualized by autoradiography. Results: Only rearrangements ofT-cell receptor (TCR) were identified in all RLH patients. Both TCR and immunoglnbulin heavy chain gene rearrangements (JH) were identified in patients, who developed from RLH to low-grade B-cell MALT lymphoma. H. pylori was separated from antral biopsied mucosa in all patients. After eradication of H.pylorl, gastroseopie and histological findings showed regression of these gastric lesions, These findings supported that proliferation of low-grade MALT lymphomas depends on an H pylori induced T-cell-mediated stimulation. ref.Okazaki K, et al. Lancet. 343:1636,1994
• hMSH2 GERMLINE MUTATIONS SCREENING IN 50 FAMILIAL CANCER AGREGATIONS. S Olschwang**, P Lat~rent-Puig*, C Boisson°, B Vogelstein#, G Thomas *°. Institut Curie, *laboratoire de G6n6tique des Tumeurs CJF9201, °unit6 de G6ndtique, 26 rue d'Ulm, 75005 Paris; #Johns Hopkins Hospital, Baltimore USA Hereditary Non PoiYposis Colorectal Cancer .is a common autosomal dominant condition predisposing to cancer. It is characterized by the development of tumors of colon, endometrium and less frequently other sites. Recently, germline mutations in HNPCC patients were detected in four different DNA-mismatch repair genes, namely hMSH2 (2p16), hMLH1 (3p21), hPMS1 (2q31-33) and hPMS2 (7p22). The spectrum of hMSH2 gene mutations has been examined among a series of French HNPCC families. Patients and Methods: Our study included 50 familial agregations of cancer. They were either colon site-specific (SS-HNPCC, 13), or non site-specific (NSS-HNPCC, 32), or Muir-Torte syndrom (3) or Cowden disease (2). Screening for hMSH2 mutations was performed on genomic DNA from one affected member Of each family using the DGGE technique. Electrophoretic variants were then directly sequenced and all available blood samples from other family 'members were checked for the corresponding mutations. Results: The entire coding sequence and all splicing junctions were screened. Among the 50 independent propositi, 16 rare and 1 frequent electrophoretic variants were found. In 11 cases, the nucleotide variation was predicted to modify the aminoacid sequence : nonsens and frameshift mutations were found in 7 cases. In 4 cases, the variant was expected to lead to an amino-acid substitution. The 6 other electrophoretic variations resulted from 2 silent nucleotide substitutions in exons 2 and 13 respectively. Segregation of the DNA variants was studied in 8 families. In 2 families in which an identical missense mutation had been found, cosegregation of the mutation with the disease did not occur. The prevalence of hMSH2 mutations appears to vary among the different subgroups of familial agregations of cancer : 7 mutations in NSS-HNPCC families (22%), 1 in SS-HNPCC families (8%) and 1 in a Muir-Torre family. Conclusion: hMSH2 germline mutation appears to be preferentially assOciated with non site-specific familial agregations of cancer. Because in most cases the mutation lead to the synthesis of a truncated protein, in absence of a functional test, the causal relationship of the detected DNA variation with the HNPCC disease can be expected; an information that is helpful in genetic diagnosis of at-risk members in affected families.
GASTROENTEROLOGY, Vol. 108, No. 4
DIET, COLONIC METABOLISM AND COLON CANCER RISK. SJD O'Keefe, M Kidd, G Noel, GO Young. Gastrointestinal Clinic, Groote Schuur Hospital, University of Cape Town, South Africa. Epidemiological studies have demonstrated that dietary items such as fibre, fish oils, vitamins C,A and E and minerals calcium and magnesium are associated with low risk whilst animal products (proteins and fats) and excessive calories are associated with higher risk of colon cancer. Recent evidence suggests that colonic flora composition and short chain fatty acid production also affect risk. In eider to investigate the relative importance of these factors in African populations with varying cancer risk, dietary intake, colonic bacterial fermentation in response to a 200g maize-meal, colonic cell differentiation measured by rectal biopsy and staining for K167, p53 and TGFas well as lhr BrDU uptake, and blood tests were performed on 20 healthy volunteers (age > 40 years) from each of the following population groups a) a high risk group consuming a Western type diet: risk 20/100 000, b) a fishing community: risk 5/100 000 and c) a black community consuming a high carbohydrate, low animal protein diet: risk 1.8/100 000. RESULTS confirmed a correlation between all four cell proliferation markers and overall cancer risk within the three populations. However, dietary intakes of fibre, vitamins A and C and calcium and magnesium were all lower in the two low risk populations. Furthermore, group mean total caloric intakes and body mass indices were similar between the three groups. Blood levels demonstrated lower vitamin levels in the two low risk populations whereas omega-3 fatty acids were significantly higher in fishermen (9.5+1.8) and in black subjects (4.3 + 1.1) than in the Westernized group (3.6+0.6), p < 0.05). In contrast omega-6 fatty acids were higher in the Westernized group (42.2 + 3.2 versus 39.1 + 1.1 and 37.4 + 1.7). Breath hydrogen response to the carbohydrate meal was marginally higher in the two low risk groups but breath methane excretion was markedly higher in blacks (37.5+7.8 versus 10.54-1.5 in Westernized group and 14.54-2.4 in fishermen, p < 001). In conclusion, the lower incidence of colon cancer in blacks eeuld be explained by the high carbohydrate diet and greater colonic bacterial methanogenesis, whilst the low rate in fishermen was associated with high omega-3 (fish oil) fatty acids. Our results would support the hypothesis that colonic health is maintained by short chain fatty acid production by colonic bacteria with the removal of excess hydrogen by methanogenie bacteria, and also the antiinflammatory and potential anti-neoplastic effects of butyrate and omega-3 fatty acids. In this study vitamins, minerals and fibre did not appear to affect risk.
DEMONSTRATION OF REMARKABLE REDUCTION 1N "DENOVO" COLON CANCER IN COLONOSCOPY FOLLOW-UP Harvey W. Olsen and William A. Lawrence, Oakland, California We have been able to demonstrate a dramatic reduction in colon cancer in patients who complied with our follow-up guidelines vs those who did not after initial colonoscopy and polypectomy. In our study population of 1441 patients who had polyps we have done follow-up colonoscopy on 371 patients who have more than 3 years follow-up (4-17 years). 176 of these patients had at least one colonoscopy within the first three years of initial exam and have had follow-up thereafter for an average of 6 years. We have 195 patients who for various reasons did not have an interval colonoscopy but whom eventually had a eolonoscopy sometime after three years of foUow-up with an average of 7 years. There was one insitu cancer identified in the follow-up group and there were nine invasive cancers in the group without initial follow up in the first three years. The incidence of cancer was approximately seven times more frequent in the non-compliant group vs those who did appropriate follow-up~ Our study data for follow-up patients is similar to the observations made in the National Polyp Study but also demonstrates the value of fo!lowup colonoscopies and polypectomies as part of the prevention program.