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PubMed2002

Use of microsatellite analysis in young patients with colorectal cancer to identify those with hereditary nonpolyposis colorectal cancer.

BACKGROUND AND OBJECTIVES: The frequency of microsatellite instability (MSI) in young patients with colorectal cancer was evaluated, including reexamination of the medical and family history of each patient, and interviews with the patients to determine any possible new occurrence of hereditary nonpolyposis colorectal cancer (HNPCC) in the patients themselves or their family members. METHODS: Fifty-three young patients (younger than 40 years of age) with colorectal cancer were selected and investigated. DNA was extracted from paraffin sections and microsatellite analysis was performed. RESULTS: The frequency of MSI among the young patients with colorectal cancer was 50.9%, which was significantly higher than the rate of 12-21% noted in older patients with colorectal cancer (P < 0.001). For the 24 young patients with colorectal cancer who did not have MSI, only one case of HNPCC kindred and two cases with a family history of cancer were identified. In contrast, among the 20 young patients with colorectal cancer who had MSI, five cases of HNPCC kindred, two cases with metachronous patients with colorectal cancer, and three cases with a family history of cancer were identified. CONCLUSION: Our results suggest that a defect in the DNA mismatch repair system may play some role in carcinogenesis in young patients with colorectal cancer. Microsatellite analysis and subsequent interviews regarding medical and family history are useful tools for efficiently identifying possible cases of HNPCC among young patients with colorectal cancer.

Adult↗
PubMed1992

Smoking and colorectal cancer risk: data from the Melbourne Colorectal Cancer Study and brief review of literature.

Lifetime smoking data were obtained from 715 colorectal cancer cases and 727 age/sex matched community controls as one part of a large, comprehensive, population-based study of colorectal cancer aetiology and survival in Melbourne, Australia, The Melbourne Colorectal Cancer Study. Statistically significant associations were found for those males smoking handrolled cigarettes and for cigar-/pipe-smoking males with colon cancer. Review of 18 previous case control studies of colorectal cancer showed an elevated risk for cigar-smoking black males in one study, a statistically non-significant increased risk for current smokers in one of 3 cohort studies and a statistically significant elevation of risk for smokers in 2 of 3 studies of adenomatous large-bowel polyps. Although at present there is insufficient evidence to link smoking with large-bowel cancer, the possibility that ingested tobacco is in some way carcinogenic for the colorectal mucosa may be worth further study.

Adenocarcinoma↗
PubMed2001

A molecular rationale for the how, when and why of colorectal cancer screening.

Colorectal cancer remains a leading cause of cancer-related mortality in the United States. Recently, colorectal cancer screening and colorectal cancer prevention have gained national attention. In response, the American Gastroenterological Association, the American College of Gastroenterology and the Agency for Healthcare Policy and Research have published recommendations for colorectal cancer screening and surveillance in patients with sporadic as well as hereditary forms of colorectal cancer. This review will focus on the basic molecular differences underlying the formation of carcinoma in patients with sporadic colorectal cancer, and the heritable syndromes of familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), and juvenile polyposis (JPS). By appreciating the molecular mechanisms underlying these four types of polyp cancer syndromes, the differences in clinical time course for progression from polyp to carcinoma and in current screening recommendations for patients with sporadic adenomas, FAP, HNPCC and JPS can be better understood.

Adenomatous Polyposis Coli↗
PubMed2005

Association between colonic screening, subject characteristics, and stage of colorectal cancer.

OBJECTIVES: Colorectal cancer remains a significant cause of mortality and morbidity in North America. Colorectal cancer survival is highly dependent on stage at diagnosis, therefore it is important to identify factors related to stage. This study evaluated the association between subject factors (e.g., colonic screening, family history) and stage of colorectal cancer at diagnosis. METHODS: Population-based colorectal cancer cases recruited by the Ontario Familial Colon Cancer Registry between 1997 and 1999 were staged according to the tumor-nodal-metastasis (TNM) staging system and classified as early (TNM I/II) or late (TNM III/IV) stage. Epidemiologic information and stage was available for 768 cases. Multivariate logistic regression was used to obtain odds ratios (OR) estimates. RESULTS: Having had screening endoscopy reduced the risk of late stage diagnosis (OR = 0.46, 95% CI 0.22-0.98). Being older (>45 yr) was associated with a reduced risk of late stage cancer (OR = 0.36, 95% CI 0.18-0.74), as was having a first degree relative with colorectal cancer (OR =0.66, 95% CI 0.46-0.95). Rural residence (OR = 1.48, 95% CI 1.01-2.17) and non-white ethnicity (OR = 3.34, 95% CI 1.20-9.36) were associated with an increased risk of late stage cancer. CONCLUSIONS: Several factors are independently associated with late stage colorectal cancer. Colorectal cancer screening awareness and education programs need to consider targeting persons most likely to present with late stage colorectal cancer.

Adult↗
PubMed1997

Interleukin-7 (IL-7) in colorectal cancer: IL-7 is produced by tissues from colorectal cancer and promotes preferential expansion of tumour infiltrating lymphocytes.

Despite increasing survival rates for patients with colorectal cancer, additional treatment options are required, including active or passive immunotherapy for patients with metastatic disease. Freshly harvested colorectal cancer specimens and in vitro cultured colorectal cancer cell lines were examined for IL-7 protein secretion in order to examine the potential role of this cytokine in the interaction between tumour cells and the host immune system. Freshly harvested colorectal cancer specimens (21/21), or normal adjacent mucosa (3/3), as well as long-term established colorectal cancer cell lines (3/4) exhibited IL-7 mRNA expression as detected by RT-PCR and confirmed by Southern Blot analysis. Freshly harvested colorectal cancer tissue (16/18), or long-term established colorectal cancer cell lines (2/4) secreted in vitro IL-7 as detected by ELISA. In contrast, breast, pancreatic, or lung cancer cell lines, as well as several haematopoietic cancer cells lines, tested negative for IL-7 mRNA and protein. The authors tested different cytokines (IL-1 beta, IL-2, IL-7, or a combination of IL-1 beta/IL-7) in vitro for the ability to expand tumour-infiltrating T lymphocytes (TIL) from individual patients (n = 9) with colorectal cancer. TIL populations were tested at day 14 after in vitro propagation for phenotypic analysis by FACS and for reactivity directed against NK and LAK sensitive target cells and autologous cancer cells as measured by cytotoxicity and cytokine release. TIL obtained from colorectal cancer lesions can be efficiently expanded in the presence of IL-7, some(3/9) of which appear to exhibit autologous tumour recognition as measured by cytolytic effector functions and by detection of IFN gamma and TNF alpha release. Detection of IL-7 mRNA expression in colorectal cancer, in normal mucosa adjacent to tumour, as well as the ability of colorectal cancer tissue to secrete IL-7, raises new questions about the biology of the host/tumour interactions in colorectal cancer.

Blotting, Southern↗
PubMed2006

Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH.

Microsatellite analysis and immunohistochemistry are commonly used initial screening tests for hereditary nonpolyposis colorectal cancer. However, tumors in roughly one-half of the patients fulfilling the Bethesda guidelines are microsatellite stable. In addition, normal mismatch repair protein expression in these tumors suggests that a defect in the mismatch repair system is unlikely. Because biallelic MYH mutations occur in patients with both high and low numbers of adenomas, we hypothesized that MYH is involved in the tumorigenesis of microsatellite stable colorectal cancers in patients without vertical transmission of disease and who fulfill the Bethesda guidelines. MYH was analyzed in 50 cancer patients and 116 healthy controls by complete genomic DNA sequencing. No biallelic germline mutations were identified. One patient was a heterozygous carrier for the p.G382D missense mutation, and another patient was a heterozygous carrier for the novel missense mutation p.Q484H. We identified six common variants, three in the coding region (p.V22M, p.Q324H, and p.S501F) and three in adjacent intronic regions (c.157+30A>G, c.462+35G>A, and c.1435-40G>C). In summary, biallelic germline mutations of MYH are unlikely to cause colorectal cancer in patients sharing clinical features with hereditary nonpolyposis colorectal cancer families without mismatch repair defect and therefore cannot fill the molecular diagnostic gap in this subgroup of Bethesda-positive patients.

Adult↗
PubMed1997

[Correlations between cell proliferating activity and apoptosis in the colorectal cancer and apoptosis in the mucosa adjacent to colorectal cancer].

To investigate the growth and progression of colorectal cancer, cell production versus cell loss in colorectal cancer was examined using the proliferating cell nuclear antigen (PCNA) positivity rate and apoptotic index (AI). Cell loss was then examined using AI in the mucosa adjacent to colorectal cancer. The higher the PCNA positivity rate, the higher the apoptotic index in colorectal cancer. These results suggested that changes in cell production and cell loss may be closely correlated and play a role in the growth and progression of colorectal cancer. In patients with advanced colorectal cancer, the mucous composition of the adjacent mucosa was classified as sialomucin-predominant. Apoptosis at the proliferating zone in the mucosa adjacent to colorectal cancer (one or two glandular ducts) was also examined using the TUNEL method. This suggests that the mucosa adjacent to cancer is involved in apoptosis.

Apoptosis↗
PubMed2004

[Chemoprevention of colorectal cancer].

Although colorectal cancer is one of the most preventable forms of cancer, it remains the second leading cause of cancer death worldwide. Primary prevention involves the identification and elimination of factors, which cause or promote colorectal cancer. The goal of screening is to prevent colorectal cancer mortality through the detection and treatment of premalignant adenomas and curable-stage cancer. Most colorectal cancers are believed to arise from adenomatous polyps. Early identification and removal of adenomas can prevent the development of colorectal cancer. Chemoprevention is the use of specific chemical compounds to prevent, inhibit, or reverse carcinogenesis. Several chemoprevention options have been investigated and confirmed as effective. Aspirin and other nonsteroidal anti-inflammatory drugs are the most widely studied agents, their use has been consistently associated with reduction in the risk of mortality and the incidence of colorectal adenomas and cancers. The selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been demonstrated to decrease the number and the size of polyps in patients with familial adenomatous polyposis syndrome. Because the gastrointestinal toxicity of coxibs is lower, it might be safer than aspirin or other non-selective nonsteroidal anti-inflammatory drugs for long-term use. This review aims to summarize the recent theoretical and practical advances in the chemoprevention of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Sporadic colorectal cancer in elderly people.

BACKGROUND/AIMS: The mechanism of the development of cancer in old age is not well understood in various cancers, especially colorectal cancer. Colorectal cancer in elderly patients often shows a high frequency of proximal colon cancer. Microsatellite instability cancers are often found in the proximal colon and show a lower incidence of p53 abnormality. While the aberrant expression of p53 is more frequent in the distal colon. To investigate the carcinogenesis of colorectal cancer in elderly patients, we studied the genetic background of these patients regarding microsatellite instability and the aberrant expression of p53. METHODOLOGY: In the present study, we examined the clinicopathological features and the frequency of p53 abnormality in elderly patients compared to younger patients, and the frequency of microsatellite instability in elderly patients. In microsatellite instability cancer, immunoreactivity of hMSH2 and hMLH1 were also examined. RESULTS: Colorectal cancer in elderly patients is associated with proximal location of the cancer (p = 0.008). Microsatellite instability was observed in only 1 case (2.8%). The immunoreactivity of hMLH1 showed negative staining in malignant glands. The frequency of aberrant expression of p53 showed no significant difference between two groups. CONCLUSIONS: We found colorectal cancer more frequently in proximal colon in elderly patients than in younger patients, and microsatellite instability frequency in elderly patients (2.8%) was lower than reported microsatellite instability frequency in sporadic colorectal cancer patients. Moreover, the frequency of aberrant expression of p53 did not differ between the two groups. In the present study, microsatellite instability appeared to be less important for the carcinogenesis of colorectal cancer in elderly patients as compared to younger patients.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Surgical treatment of colorectal cancer metastasis.

Colorectal cancer is one of the most common solid tumors affecting people around the world. A significant proportion of patients with colorectal cancer will develop or will present with liver metastases. In some of these patients, the liver is the only site of metastatic disease. Thus, surgical treatment approaches are an appropriate and important treatment option in patients with liver-only colorectal cancer metastases. Resection of colorectal cancer liver metastases can produce long-term survival in selected patients, but the efficacy of liver resection as a solitary treatment is limited by two factors. First, a minority of patients with liver metastases have resectable disease. Second, the majority of patients who undergo successful liver resection for colorectal cancer metastases develop recurrent disease in the liver, extrahepatic sites, or both. In this paper, in addition to the results of liver resection for colorectal cancer metastases, we will review the results of thermal ablation. Each of these surgical treatment modalities can produce long-term survival in a subset of patients with liver-only colorectal cancer metastases, whereas administration of systemic or regional chemotherapy rarely results in long-term survival in these patients. While surgical treatments provide the best chance for long-term survival or, in some cases, the best palliation in patients with colorectal cancer liver metastases, it is clear that further improvements in patient outcome will require multimodality therapy regimens. Modern surgical treatment of colorectal liver metastases can be performed safely with low mortality and transfusion rates, and surgical treatment should be considered in patients with disease confined to their liver.

Catheter Ablation↗
PubMed2005

Non-invasive detection of c-myc p64, c-myc p67 and c-erbb-2 in colorectal cancer.

OBJECTIVE: Colorectal cancer is a major cause of cancer mortality in the industrialized nations in the West. Because mortality is closely related to the stage of the disease at the time of diagnosis, detection at an early stage is likely to result in improved recovery rates. Since current diagnostic procedures such as colonoscopy are invasive and the fecal occult blood test (FOBT) lacks sensitivity and specificity for the detection of early lesions, the development of non-invasive methods based on molecular markers of neoplasia can lead to earlier diagnosis and more favorable outcomes for patients with colorectal cancer. Recent advances in the technology for isolating colonocytes from stool (SCSR (somatic cell sampling and recovery)) provide a non-invasive tool for the study of biomarkers expressed in colorectal cancer. The aim of this study was to detect mRNA expression of three biomarkers: (c-erbb-2 and two forms of c-myc: p64 and p67) in fecal colonocytes and to evaluate its use in diagnosing colorectal cancer. MATERIAL AND METHODS: Colonocytes (SCSR cells) were isolated from stools from 30 subjects: 15 colorectal cancer patients and 15 normal controls. One cancer patient was excluded from the final data analysis because the tumor was a gastrointestinal lymphoma. Each sample yielded two fractions: a pellet and an interphase. Expression of c-myc p64, c-myc p67 and c-erbb-2 mRNA was evaluated in each of the fractions by reverse transcriptase-polymerase chain reaction (RT-PCR). A marker was considered positive upon detecting an amplicon of the expected size in agarose gel electrophoresis. RESULTS: c-myc p64 mRNA expression was observed in both fractions in 78.5% of colorectal cancer patients, compared with 13.3% in the control group (p=0.009). For c-myc p67, 78.6% of the colorectal cancer patients showed mRNA expression in both fractions in comparison with only 13.3% of the controls (p=0.003). C-erbb-2 showed no significant difference in mRNA expression between colorectal cancer and controls. When the data were analyzed for co-expression of c-myc p64 and c-myc p67, in both pellet and interphase, sensitivity was 64% and specificity was 100%. CONCLUSIONS: Fecal colonocytes isolated by somatic cell sampling and recovery (SCSR) technology could be used for the non-invasive assessment of the expression of biomarkers of colon cancer such as c-myc p64, c-myc p67 and c-erbb-2. The expression of c-myc p64 and c-myc p67 in colonocytes showed a significant association with colorectal cancer and may be helpful as a biomarker for the non-invasive detection of colorectal cancer.

Aged↗
PubMed1992

[Multivisceral resection of colorectal cancer--experiences of the Colorectal Cancer Study Group].

Between 1984 and 1986, 2341 patients with colorectal carcinoma from 7 German institutions entered the colorectal carcinoma study group (SGCRC). In 197 of 2053 patients with radical resections, the operation was extended by multivisceral resection. The two groups of patients were comparable in age, preoperative risk factors, postoperative morbidity, and mortality. Long-term results showed no statistically significant difference in survival according to the 5-year survival rates, calculated by the actuarial method when curative resections in UICC stage II and III were compared. After curative resection (R0), the presence or absence of intraoperative tumor-cell dissemination could be identified as a significant prognostic factor. The analysis of T4 tumors without distant metastases or serosal penetration showed a significant correlation between the percentage of patients treated by R0 resection and long-term survival in the different participating institutions.

Abdominal Neoplasms↗
PubMed2007

Chemotherapy for colorectal cancer prior to liver resection for colorectal cancer hepatic metastases does not adversely affect peri-operative outcomes.

BACKGROUND: Systemic chemotherapy is being used increasingly in patients with colorectal cancer. The effects of prior systemic adjuvant or palliative chemotherapy on morbidity following hepatic resection for metastases are not well defined. OBJECTIVES: To assess the peri-operative impact of systemic chemotherapy on liver resection for colorectal cancer hepatic metastases. METHODS: Ninety-six resections for colorectal cancer hepatic metastases performed from July 2001 to July 2003 (93% > or =2 segments) were reviewed. Pre-operative demographics, peri-operative features, and post-operative outcomes were collected prospectively. Type of chemotherapy and the temporal relationship of chemotherapy to the liver resection were analyzed. RESULTS: Fifty-three of 96 patients (55%) received a mean of 5.7 cycles (6.1 months) of systemic chemotherapy prior to hepatic resection, with a median interval of 12 months from end of chemotherapy to liver resection (range 1-75 months). Thirty-five received 5-fluorouracil/leucovorin (5-FU/LV) alone, nine had irinotecan (CPT-11) in addition to 5-FU/LV, and nine were not specified. Pre-operative age, sex, co-morbidities, ASA score, biochemical and liver enzyme profiles, tumor number, and extent and technique of hepatic resection were the same in the chemotherapy and non-chemotherapy cohorts. Mean tumor size was smaller (4.5 cm vs. 5.8 cm) and synchronous metastases were half as common (25% vs. 49%) in the chemotherapy group. Liver resection operative time was equivalent (270 min) in the two groups. Higher estimated blood loss (EBL) (1,000 ml vs. 850 ml), but fewer transfusions (23% vs. 15%) were associated with the chemotherapy group. Although not statistically significant, post-operative liver enzyme peaks were higher in the chemotherapy group (AST = 402 U/L vs. 302 U/L, P = 0.09 and ALT = 433 U/L vs. 312 U/L, P = 0.1). Peak changes in INR and serum bilirubin did not differ. Complications and length of stay (LOS) did not differ between the groups. The only post-operative death was in the non-chemotherapy group. Interestingly, hepatic steatosis was present in 28% of the non-chemotherapy cases and 57% of the chemotherapy resection specimens (P = 0.005) and was marked (>30%) in 7% and 10%, respectively. Further analysis of the chemotherapy group based on the interval between completion of chemotherapy and the hepatic resection (<6 months, 7-12 months, 1-2 years, and >2 years) revealed a trend towards worse outcomes in most categories for those in the >2 years cohort. When comparing the 5-FU/LV alone, to the CPT-11 group there were no significant differences except higher intra-operative blood loss in the group receiving 5-FU/LV alone (1,295 ml vs. 756 ml, P = 0.01). CONCLUSION: Despite variations in biochemical function and hepatic steatosis, short-term clinical outcomes are not affected by the administration of chemotherapy prior to hepatic resection. Furthermore, there is no detrimental effect of close timing of chemotherapy prior to resection, and there are no appreciable differences between irinotecan containing regimes and more traditional 5-FU-only based therapies, although the subset sample sizes were small in this study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

The Melbourne Colorectal Cancer Study. Characterization of patients with a family history of colorectal cancer.

The characteristics of 702 colorectal cancer patients are described in relation to the presence of absence of a family history of colorectal cancer in near relatives. No statistically significant associations were found between those with a family history of colorectal cancer and age at detection, sex, country of birth, religion, number of cancers (single, synchronous, or metachronous), previously removed benign colorectal polyps, and adenomatous polyps found in the resection specimen. The family history rate of colorectal cancer for colon cancer cases was statistically significantly higher than for rectal cancer cases (chi 2(1) = 3.8, P = .05) and there was a gradient of decreasing risk from colon to rectum. The family history rate of colorectal cancer in parents of those who were less than 50 years old was twice that of those 50 or older (P = .07), consistent with the view that earlier age of onset is a characteristic of those with a family history of colorectal cancer. There was a statistically significantly higher family history rate of colorectal cancer in respondents who knew of the disease compared with those who did not (chi 2(1) = 5.5, P less than .05). It is unclear if this effect represents recall bias or self-selection bias. In contrast, the rates for a family history of heart disease and stroke were similar, irrespective of the respondent's knowledge of their colorectal cancer status. Thus in the Melbourne study, the family history rate of colorectal cancer was higher in colon cancer than in rectal cancer, there was a decreasing gradient of risk from colon to rectum, and a tendency for earlier age of onset of colorectal cancer in those with a history of this cancer in a parent.

Age Factors↗
PubMed2000

Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.

BACKGROUND: Colorectal cancer can arise through two distinct mutational pathways: microsatellite instability or chromosomal instability. We tested the hypothesis that colorectal cancers arising from the microsatellite-instability pathway have distinctive clinical attributes that affect clinical outcome. METHODS: We tested specimens of colorectal cancer from a population-based series of 607 patients (50 years of age or younger at diagnosis) for microsatellite instability. We compared the clinical features and survival of patients who had colorectal cancer characterized by high-frequency microsatellite instability with these characteristics in patients who had colorectal cancers with microsatellite stability. RESULT: We found high-frequency microsatellite instability in 17 percent of the colorectal cancers in 607 patients, and in a multivariate analysis, microsatellite instability was associated with a significant survival advantage independently of all standard prognostic factors, including tumor stage (hazard ratio, 0.42; 95 percent confidence interval, 0.27 to 0.67; P< 0.001). Furthermore, regardless of the depth of tumor invasion, colorectal cancers with high-frequency microsatellite instability had a decreased likelihood of metastasizing to regional lymph nodes (odds ratio, 0.33; 95 percent confidence interval, 0.21 to 0.53; P< 0.001) or distant organs (odds ratio, 0.49; 95 percent confidence interval, 0.27 to 0.89; P=0.02). CONCLUSION: High-frequency microsatellite instability in colorectal cancer is independently predictive of a relatively favorable outcome and, in addition, reduces the likelihood of metastases.

Adult↗
PubMed2005

Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers.

In colorectal cancer, the immune response is particularly pronounced against tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H tumors accumulate mutations affecting microsatellites located within protein encoding regions (coding microsatellites, cMS), which lead to translational shifts of the respective reading frames. Consequently, novel tumor-specific frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor cells, thus eliciting effective cytotoxic immune responses. To analyze whether the immunoselective pressure was reflected by the phenotype of MSI-H colorectal cancer cells, we compared here the expression of antigen processing machinery (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly developed APM component-specific monoclonal antibodies. In addition, we did a systematic analysis of mutations at cMS located within APM genes and beta2-microglobulin (beta2m). Total HLA class I antigen loss was observed in 12 (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at cMS of beta2m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA class I antigen processing and presentation seem to be significantly more frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer the immunoselective pressure leads to the outgrowth of cells with defects of antigen presentation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer.

BACKGROUND & AIMS: Identification of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of colonoscopy and polypectomies. We evaluated the efficacy of screening in a controlled trial over 15 years. METHODS: Incidence of CRC and survival were compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic screening at 3-year intervals was arranged for 133 subjects; 119 control subjects had no screening. Genetic testing was offered to subjects in whose families the causative mutation was known. RESULTS: CRC developed in 8 screened subjects (6%) compared with 19 control subjects (16 %; P = 0.014). The CRC rate was reduced by 62%. In mutation-positive subjects alone, the CRC rates were 18% in screened subjects and 41% in controls (P = 0.02). The decrease resulted from the removal of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with unknown mutation status (40%). All CRCs in the study group were local, causing no deaths, compared with 9 deaths caused by CRC in the controls. The overall death rates were 10 vs. 26 subjects in the study and control groups (P = 0.003), 4 vs. 12 in mutation-positive subjects (P = 0.05). CONCLUSIONS: Colonoscopic screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families.

Adaptor Proteins, Signal Transducing↗