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K Kämpjärvi,
N Mäkinen,
O Kilpivaara,
J Arola,
H-R Heinonen,
J Böhm,
O Abdel-Wahab,
H J Lehtonen,
L M Pelttari,
M Mehine,
H Schrewe,
H Nevanlinna,
R L Levine,
P Hokland,
T Böhling, J-P Mecklin,
R Bützow,
L A Aaltonen,
P Vahteristo
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ABSTRACT: Background:Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types.Methods:The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)).Results:Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val).Conclusion:Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.
British Journal of Cancer 11/2012; 107(10):1761-5. · 5.04 Impact Factor
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A D Beggs,
A R Latchford,
H F A Vasen,
G Moslein,
A Alonso,
S Aretz,
L Bertario,
I Blanco,
S Bülow,
J Burn, [......],
W Hyer,
M Ponz de Leon,
L Renkonen-Sinisalo,
J R Sampson,
A Stormorken,
S Tejpar,
H J W Thomas,
J T Wijnen,
S K Clark,
S V Hodgson
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ABSTRACT: Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.
Gut 07/2010; 59(7):975-86. · 10.11 Impact Factor
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H F A Vasen,
G Möslein,
A Alonso,
S Aretz,
I Bernstein,
L Bertario,
I Blanco,
S Bulow,
J Burn,
G Capella, [......],
H J W Thomas,
J Wijnen,
J Lubinski,
H Järvinen,
E Claes,
K Heinimann,
J A Karagiannis,
A Lindblom,
I Dove-Edwin,
H Müller
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ABSTRACT: Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.
Familial Cancer 09/2009; 9(2):109-15. · 1.30 Impact Factor
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ABSTRACT: Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.
Carcinogenesis 07/2008; 29(7):1351-9. · 5.70 Impact Factor
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H F A Vasen,
G Möslein,
A Alonso,
S Aretz,
I Bernstein,
L Bertario,
I Blanco,
S Bülow,
J Burn,
G Capella, [......],
Y Parc,
R Phillips,
S K Clark,
M Ponz de Leon,
L Renkonen-Sinisalo,
J R Sampson,
A Stormorken,
S Tejpar,
H J W Thomas,
J Wijnen
[show abstract]
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ABSTRACT: BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.
Gut 05/2008; 57(5):704-13. · 10.11 Impact Factor
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ABSTRACT: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy.
In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families.
After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach.
In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.
Journal of Medical Genetics 12/2007; 44(11):732-8. · 6.36 Impact Factor
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ABSTRACT: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy.
To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. Subjects and
The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status.
This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI.
The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.
Gut 07/2007; 56(7):926-33. · 10.11 Impact Factor
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H F A Vasen,
G Möslein,
A Alonso,
I Bernstein,
L Bertario,
I Blanco,
J Burn,
G Capella,
C Engel,
I Frayling, [......],
F J Hes,
S Hodgson, J-P Mecklin,
P Møller,
F Nagengast,
Y Parc,
L Renkonen-Sinisalo,
J R Sampson,
A Stormorken,
J Wijnen
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[hide abstract]
ABSTRACT: Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.
Journal of Medical Genetics 07/2007; 44(6):353-62. · 6.36 Impact Factor
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ABSTRACT: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.
Oncogene 05/2007; 26(17):2513-7. · 6.37 Impact Factor
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P Laiho,
A Kokko,
S Vanharanta,
R Salovaara,
H Sammalkorpi,
H Järvinen, J-P Mecklin,
T J Karttunen,
K Tuppurainen,
V Davalos,
S Schwartz,
D Arango,
M J Mäkinen,
L A Aaltonen
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ABSTRACT: Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.
Oncogene 02/2007; 26(2):312-20. · 6.37 Impact Factor
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E Volikos,
J Robinson,
K Aittomäki, J-P Mecklin,
H Järvinen,
A M Westerman,
F W M de Rooji,
T Vogel,
G Moeslein,
V Launonen,
I P M Tomlinson,
A R J Silver,
L A Aaltonen
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ABSTRACT: LKB1/STK11 germline mutations cause Peutz-Jeghers syndrome (PJS). The existence of a second PJS locus is controversial, the evidence in its favour being families unlinked to LKB1 and the low frequency of LKB1 mutations found using conventional methods in several studies. Exonic and whole gene deletion or duplication events cannot be detected by routine mutation screening methods.
To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening.
From an original cohort of 76 patients, 48 were found to have a germline mutation by direct sequencing; the remaining 28 were examined using multiplex ligation dependent probe amplification (MLPA) analysis to detect LKB1 copy number changes.
Deletions were found in 11 of the 28 patients (39%)--that is, 14% of all PJS patients (11/76). Five patients had whole gene deletions, two had the promoter and exon 1 deleted, and in one patient exon 8 was deleted. Other deletions events involved: loss of exons 2-10; deletion of the promoter and exons 1-3; and loss of part of the promoter. No duplications were detected. Nine samples with deletions were sequenced at reported single nucleotide polymorphisms to exclude heterozygosity; homozygosity was found in all cases. No MLPA copy number changes were detected in 22 healthy individuals.
These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76). It is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of PJS patients in clinical practice.
Journal of Medical Genetics 06/2006; 43(5):e18. · 6.36 Impact Factor
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P Alhopuro,
S K Ylisaukko-Oja,
W J Koskinen,
P Bono,
J Arola,
H J Järvinen, J-P Mecklin,
T Atula,
R Kontio,
A A Mäkitie,
S Suominen,
I Leivo,
P Vahteristo,
L-M Aaltonen,
L A Aaltonen
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ABSTRACT: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans.
We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309.
Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials.
SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.
Journal of Medical Genetics 10/2005; 42(9):694-8. · 6.36 Impact Factor
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M Kruhøffer,
J L Jensen,
P Laiho,
L Dyrskjøt,
R Salovaara,
D Arango,
K Birkenkamp-Demtroder,
F B Sørensen,
L L Christensen,
L Buhl, [......],
H Järvinen,
T Thykjaer,
F P Wikman,
F Bech-Knudsen,
M Juhola,
N N Nupponen,
S Laurberg,
C L Andersen,
L A Aaltonen,
T F Ørntoft
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ABSTRACT: The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.
British Journal of Cancer 07/2005; 92(12):2240-8. · 5.04 Impact Factor
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H Rasinperä,
C Forsblom,
N S Enattah,
P Halonen,
K Salo,
M Victorzon, J-P Mecklin,
H Järvinen,
S Enholm,
G Sellick,
H Alazzouzi,
R Houlston,
J Robinson,
P-H Groop,
I Tomlinson,
S Schwartz,
L A Aaltonen,
I Järvelä
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ABSTRACT: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T(-13910) polymorphism and colorectal cancer in Finnish, British, and Spanish populations.
A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T(-13910) variant by polymerase chain reaction minisequencing.
The C/C(-13910) genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07-1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations.
Low lactase enzyme activity, defined by genotyping of the C/T(-13910) variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.
Gut 06/2005; 54(5):643-7. · 10.11 Impact Factor
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Journal of Medical Genetics 08/2004; 41(7):e95. · 6.36 Impact Factor
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Journal of Medical Genetics 06/2003; 40(5):e73. · 6.36 Impact Factor
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ABSTRACT: We investigated the volume of dyspeptic patients referred by general practitioners (GPs) to upper gastrointestinal endoscopy and the impact on endoscopic findings. We also examined the correlation between clinical symptoms and endoscopic findings.
We collected data on patients sent for upper gastrointestinal endoscopy by GPs of 30 healthcare centres in 1996 in our hospital referral area of 260,000 inhabitants. In addition, national and local cancer registries were used to enumerate the gastric cancer cases detected in 1996.
The study population consisted of 3378 patients, mean age 58 years (interquartile range 25 years, male:female 1:1.3). Among the 30 healthcare centres, referral volumes for upper gastrointestinal endoscopy varied from 0.6 to 9.2 per 1000 inhabitants per year (median 3.3/1000/year). In healthcare units with 'high' (> or = 3.3/1000/year, 15 healthcare units, 1297 patients) and 'low' (<3.3/1000/year, 15 healthcare units, 2065 patients) referral volumes, the detection rates were as follows: duodenal ulcer (DU) 3.5% (n = 46) versus 4.0% (n = 83, P = 0.5), gastric ulcer (GU) 4.9% (n = 64) versus 5.3% (n = 110, P = 0.6), gastropathy 43.8% (n = 568) versus 35.6% (n = 736, P < 0.001), gastric cancer 0.5% (n = 6) versus 0.5% (n = 11, P = 0.8), gastric polyps 2.4% (n = 31) versus 1.5% (n = 30, P < 0.05). Independent risk factors for gastric cancer were age (OR 6.5 per decade, 95% CI 2.4-17.9), male sex (OR 5.5, 95% CI 1.8-17.1) and alarming symptoms and/or signs (OR 3.6, 95% CI 1.2-10.7); for GU, Helicobacter pylori (OR 2.6, 95% CI 1.9-3.5) and alarming symptoms (OR 2.0, 95% CI 1.4-2.7); for DU, male sex (OR 1.6, 95% CI 1.1-2.2) and H. pylori (OR 3.9, 95% CI 2.7-5.5); and for gastric polyp(s), age (OR 2.0 per decade, 95% CI 1.1-3.5) and high referral volume (OR 1.7, 95% CI 1.0-2.0). A high referral volume did not associate positively either with the number of peptic ulcers or gastric cancer.
Alarm symptoms associate strongly with significant gastric lesions such as GU and cancer. Increased referral volume results in an increased number of gastropathy and gastric polyp(s), but not of peptic ulcer or cancer.
Scandinavian Journal of Gastroenterology 01/2003; 38(1):109-13. · 2.02 Impact Factor
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ABSTRACT: The DNA mismatch repair gene mutations underlying hereditary non-polyposis colorectal cancer syndrome (HNPCC) also predispose, besides colorectal and endometrial cancer, to gastric cancer. usually of the intestinal type. The carcinogenetic pathway behind the elevated gastric cancer risk is largely unknown.
The aim of this study was to determine whether there are any premalignant lesions to search for in gastric surveillance in HNPCC by comparing gastric histopathology between mutation-positive and mutation-negative family members. We searched for differences in occurrence of Helicobacter pylori, inflammation, atrophy, intestinal metaplasia and dysplastic changes. Upper gastrointestinal endoscopy was performed for 73 mutation-positive and 32 mutation-negative family members.
One case of duodenal cancer was detected in the mutation-positive group, but no gastric neoplastic lesions were seen in either group. There were no differences in the occurrence of polyps, H. pylori, inflammation, activity, atrophy nor intestinal metaplasia tested with binaric, logistic, regression analysis.
We conclude that surveillance gastroscopy may not be beneficial in HNPCC, since neither cases of early cancer nor premalignant lesions could be detected in our series of 73 mutation-positive subjects.
Scandinavian Journal of Gastroenterology 06/2002; 37(5):574-7. · 2.02 Impact Factor
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ABSTRACT: The purpose of this study was to examine the outcome of patients to whom a temporary stoma was constructed in our institution.
The outcome of patients operated on over an 8-year period was prospectively examined. Special attention was given to the influence of age on complications and closure of stomas.
Between 1989 and 1996, a total of 349 intestinal stomas were constructed in 342 patients. In 141 of these patients, the stoma could be considered as temporary. The 30-day mortality rate was 7%. The overall complication rate was 50%. Pure stoma-related complications were observed in 12% of the patients. The final closure rate of temporary stomas was 67%. The closure rate was significantly higher if the temporary stomas were of the double-barrel type. There was no significant difference in the closure rate between patients with benign and malignant diseases, but the rate decreased significantly in age groups over 70 years.
Forty percent of stomas constructed are considered as temporary, but only two-thirds of temporary stomas are closed subsequently. Especially end stomas tend to become permanent in patients over 70 years of age, although the morbidity rates of stoma closure do not differ from those of younger patients.
Digestive Surgery 02/2002; 19(1):45-51. · 1.22 Impact Factor
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Journal of Medical Genetics 12/2001; 38(11):787-92. · 6.36 Impact Factor
