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Steven Gallinger

Publications and source records attributed to Steven Gallinger.

At least 19 recordsLinked to original sources
PubMed2007

Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients.

OBJECTIVES: MYH is a member of the DNA base excision repair (BER) pathway and mutations of this gene predispose to the development of colorectal neoplasia in an autosomal recessive transmission pattern. Our objective was to determine the significance of MYH mutations in a series of Canadian patients with multiple adenomas. METHODS: We screened for germline MYH mutations (by dHPLCO) in 20 clinic-based multiple adenoma patients who were adenomatous polyposis coli (APC) mutation-negative. Suspected mutations were confirmed by sequence analysis. RESULTS: Six of 20 (30%) patients carried pathogenic biallelic MYH mutations, 1 Y165C homozygote and 5 compound heterozygotes of other sequence variants. We identified three novel variants, Q377X, 1314delA, and P281L, which are likely pathogenic. Twenty-nine relatives of the Y90X/1103delC compound heterozygous carrier were also screened for germline MYH mutations, and 1 homozygous and 14 heterozygous carriers were identified. CONCLUSIONS: Among patients with multiple adenomas, biallelic MYH mutations account for approximately 30% of APC mutation negative cases and two thirds of these carry mutations other than the "common" Y165C and G382D variants. Clinical screening algorithms which focus only on the Y165C and G382D alleles are inadequate since additional pathogenic mutations may be identified by screening the entire gene.

Adenocarcinoma↗
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↗
PubMed2007

Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.

Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-beta and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)-Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-beta/Wnt cooperative targets. Our results indicate that the TGF-beta and Wnt/beta-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression.

Adenoma↗
PubMed2007

Impact of regional lymph node evaluation in staging patients with periampullary tumors.

BACKGROUND: Two distinct lymph nodes reproducibly assessed by computed tomography for the evaluation of periampullary tumors are the common bile duct (CBD) node and the gastroduodenal artery (GDA) node. We examined whether radiographical enlargement of either lymph node predicts tumor resectability, nodal metastasis, or patient survival. METHODS: Ninety-four consecutive patients underwent attempted curative resection of periampullary tumors between September 2001 and June 2003. A single radiologist recorded in a retrospective, blinded fashion the short- and long-axis measurements of the CBD and GDA nodes. RESULTS: Sixty-one percent (n = 57) of tumors were resectable by pancreaticoduodenectomy. Overall, actual 6-, 12-, and 18-month survival was 87%, 68%, and 63%, respectively. Enlarged radiographical nodal size by either axis was not associated with the presence of metastasis to these lymph nodes or with reduced overall patient survival. Only a CBD node short-axis size >10 mm predicted unresectability (odds ratio, 3.2; P = .036). Liver metastasis and/or carcinomatosis were present in 43% of unresectable patients, and this was associated with decreased survival at both 1 year (25% vs. 77%; P < .001) and 18 months (19% vs. 72%; P <.001). A pathologic diagnosis of metastasis to the GDA node, but not the CBD node, was associated with a similarly decreased survival (1 year: 33% vs. 78%, P = .028; 18 months: 22% vs. 70%, P = .023). CONCLUSIONS: For presumed periampullary malignancy, a CBD node short-axis size >10 mm predicts tumor unresectability. Metastatic disease to the GDA node, particularly for pancreatic adenocarcinoma, portends a poor prognosis equivalent to that of hepatic or peritoneal spread. Given these findings, radiographical CBD lymph node measurements may guide selection for performing laparoscopic staging with or without ultrasonography in conjunction with GDA nodal biopsy in patients with periampullary malignancy.

Abdomen↗
PubMed2006

Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: a phase I-II study.

PURPOSE: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. METHODS AND MATERIALS: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m(2) gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m(2) within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m(2)) and 52.5 Gy RT within 6 weeks. RESULTS: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. CONCLUSION: Biweekly gemcitabine (40 mg/m(2)) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.

Adult↗
PubMed2006

A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.

Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

AC133 Antigen↗
PubMed2006

Prediction of germline mutations and cancer risk in the Lynch syndrome.

CONTEXT: Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost. OBJECTIVE: To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer. DESIGN, SETTING, AND PATIENTS: External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability. MAIN OUTCOME MEASURE: Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy. RESULTS: In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines. CONCLUSIONS: MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Menstrual and reproductive risk factors and risk for gastric adenocarcinoma in women: findings from the canadian national enhanced cancer surveillance system.

PURPOSE: The role of menstrual and reproductive risk factors for gastric cancer has not been well studied. METHODS: This population-based case-control study included 326 women aged 20 to 74 years with gastric adenocarcinoma. Controls were 326 women frequency matched on age. Data for reproductive and/or hormonal exposure and gastric cancer risk factors were captured through self-administered questionnaire. RESULTS: Later age at menarche was associated with increased risk for adenocarcinoma compared with menarche onset at younger than 13 years of age (13 to 14 years: odds ratio [OR], 1.45; 95% confidence interval [CI], 1.00-2.10; > or =15 years: OR, 1.93; 95% CI, 1.19-3.13). Compared with premenopause, natural menopause was associated with increased risk for adenocarcinoma (OR, 1.99; 95% CI, 0.98-4.05). Compared with nulliparity, 4 or more births were associated with decreased risk for gastric cancer, as was being pregnant for 5 months or longer if the first pregnancy occurred at younger than 24 years (OR, 0.55; 95% CI, 0.31-0.96) or 25 years or older (OR, 0.67; 95% CI, 0.38-1.18). Oral contraceptives and hormone replacement therapy were associated with a non-statistically significant decreased risk. CONCLUSION: These findings suggest that hormonal factors associated with greater exposure to estrogen and/or progesterone may be associated with decreased risk for gastric cancer.

Adenocarcinoma↗
PubMed2006

Survival after hepatic resection for colorectal metastases: a 10-year experience.

BACKGROUND: Metastatic colorectal cancer is a major cause of cancer death in North America. Hepatic resection offers the potential for cure in selected patients. We report the long-term outcomes of patients who underwent hepatic resection for colorectal metastases over a 10-year period at a single hepatobiliary surgical oncology center. METHODS: All patients who underwent liver resection for metastatic colorectal cancer between 1992 and 2002 were identified. Data were retrospectively obtained through chart review. Major outcome variables were disease-free survival and overall survival. Risk factors for disease recurrence and mortality were identified by multivariate analysis by using the Cox proportional hazard method. RESULTS: A total of 423 hepatectomies were performed for metastatic colorectal cancer. Most operations (n = 276; 65%) were major (four or more segments) hepatectomies. Perioperative morbidity occurred in 74 (17%) patients. There were seven (1.6%) perioperative deaths. The disease-free survival at 1, 5, and 10 years was 64%, 27%, and 22%, respectively. The overall survival at 1, 5, and 10 years was 93%, 47%, and 28%, respectively. Multivariate analysis identified four negative predictive factors for overall survival (hazard ratio; 95% confidence interval): a positive surgical margin (2.9; 1.5-5.3), large metastases (>5 cm; 1.5; 1.1-2.0), multiple metastases (1.4; 1.1-1.9), and age >60 years (1.4; 1.1-1.9). CONCLUSIONS: Hepatic resection for metastatic colorectal cancer is safe and provides good long-term overall survival rates of 47% at 5 years and 28% at 10 years. An aggressive approach is justified by the low operative mortality rate and good long-term survival, even in individuals with multiple bilobar metastases.

Adult↗
PubMed2006

Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma.

BACKGROUND: Patients with hepatic and pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. We examined the longterm outcomes of patients who underwent both lung and liver resections for colorectal metastases over a 10-year period. STUDY DESIGN: Four hundred twenty-three hepatectomies were performed for metastatic CRC between 1992 and 2002 at two university-affiliated hospitals. Patients who underwent both lung and liver resections for metastatic CRC were studied. Demographic, perioperative, and survival data were evaluated by retrospective chart review. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis and survival curves were compared using the log-rank test. RESULTS: Thirty-nine patients underwent both lung and liver resections for metastatic CRC. Eleven patients (28%) underwent staged liver and lung metastasectomy from synchronously identified metastases. Twenty-eight patients (72%) underwent sequential metastasectomy because of recurrent disease. The median disease-free and overall survivals after initial metastasectomy were 19.8 and 87 months, respectively. Serial metastasectomy was common in this patient population. The mean number of metastasectomies performed was 2.6 per patient (range 1 to 4). There was no difference in overall survival for patients with synchronous versus metachronous presentation of liver and lung metastases (p=0.45). The site of first recurrence after initial metastasectomy was, most commonly, the lung (n=19, 49%), followed by the liver (n=8, 21%). Nineteen patients (49%) underwent subsequent resections for recurrences. Seven patients (18%) underwent 2 or more liver resections for recurrent disease, and 12 (31%) underwent multiple lung resections. CONCLUSIONS: An aggressive multidisciplinary surgical approach should be undertaken for recurrent CRC metastases. In selected patients, serial metastasectomy for recurrent metastatic disease is safe and results in excellent longterm survival after CRC resection.

Adult↗
PubMed2006

Surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer: an evidence-based review.

PURPOSE: Surveillance colonoscopy plays an important role in the management of asymptomatic patients known to carry and suspected of carrying hereditary nonpolyposis colorectal cancer gene mutations. Although the shortest interval between surveillance examinations may seem to offer the most benefit to patients, excessive use of this procedure may have unwanted consequences. This study was designed to evaluate the evidence and make recommendations regarding the optimal frequency of surveillance colonoscopy and the age at which to initiate surveillance based on the best available evidence. METHODS: MEDLINE was searched for all articles assessing surveillance colonoscopy from 1966 to 2004 by using the MESH terms "hereditary nonpolyposis colorectal cancer" and "screening." The evidence was systematically reviewed and a critical appraisal of the evidence was performed. RESULTS: There are no randomized, controlled, clinical trials examining the frequency of surveillance colonoscopy in hereditary nonpolyposis colorectal cancer. Three cohort studies were identified for review. There is one cohort study of good quality that provides evidence that surveillance colonoscopy every three years in patients with hereditary nonpolyposis colorectal cancer reduces the risk of developing colorectal cancer and the risk of death. The two remaining cohort studies provide poor evidence on which to make a recommendation. CONCLUSIONS: The best available evidence supports surveillance with complete colonoscopy to the cecum every three years in patients with hereditary nonpolyposis colorectal cancer (B recommendation). There is no evidence to support or refute more frequent screening. Further research is required to examine the potential harms and benefits of more frequent screening. However, given the potential for rapid progression from adenoma to carcinoma and missing lesions at colonoscopy, there is consensus that screening more frequently than every three years is required.

Colonoscopy↗
PubMed2006

Dietary phytoestrogen intake is associated with reduced colorectal cancer risk.

Evidence suggests dietary phytoestrogens may reduce the risk of certain hormonal cancers (e.g. breast and prostate). There is a paucity of data regarding phytoestrogens and colorectal cancer risk. Phytoestrogens are plant compounds with estrogen-like activities. Main classes include isoflavones (found in legumes such as soy) and lignans (found in grains, seeds, nuts, fruits, and vegetables). Although isoflavones have dominated phytoestrogen cancer research, lignans may be more relevant to North American diets. Food questionnaires and analytic databases have recently been modified to incorporate some lignan information. We conducted a case-control study to evaluate the association between phytoestrogen intake and colorectal cancer risk. Colorectal cancer cases were diagnosed in 1997-2000, aged 20-74 y, identified through the population-based Ontario Cancer Registry, and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex and age-group matched random sample of the population of Ontario. Epidemiologic and food frequency questionnaires were completed by 1095 cases and 1890 control subjects. Multivariate logistic regression analysis was used to obtain adjusted odds ratio (OR) estimates. Dietary lignan intake was associated with a significant reduction in colorectal cancer risk [OR (T3 vs. T1) = 0.73; 95% CI: 0.56, 0.94], as was isoflavone intake [OR (T3 vs. T1) = 0.71; 95% CI: 0.58, 0.86]. We evaluated interactions between polymorphic genes that encode enzymes possibly involved in metabolism of phytoestrogens (CYPs, catechol O-methyl transferase, GSTs, and UGTs) and found no significant effect modification with respect to phytoestrogen intake. This finding that phytoestrogen intake may reduce colorectal cancer risk is important, because dietary intake is potentially modifiable.

Colorectal Neoplasms↗
PubMed2006

Natural history and chemotherapy effectiveness for advanced adenocarcinoma of the small bowel: a retrospective review of 113 cases.

BACKGROUND: Small bowel adenocarcinoma is a rare cancer that has generally been considered resistant to chemotherapy, although little has been published on the role of chemotherapy. A retrospective analysis was conducted of patients with advanced small bowel adenocarcinoma to explore chemotherapy use, and gain knowledge for ongoing management and future clinical trials. PATIENTS AND METHODS: All patients with advanced adenocarcinoma of the small bowel treated at Princess Margaret Hospital (PMH) between 1986 and 2004 were identified through the cancer registry. The medical records were reviewed for patient characteristics, treatment and outcome data. Survival statistics were estimated using the Kaplan Meier survival curves and Cox proportional regression model. RESULTS: Data on 113 patients was reviewed. Forty-four patients received palliative chemotherapy with an overall response rate (ORR) of 36% during a first or second line regimen (9% complete responses and 27% partial responses). Newer chemotherapy regimens including gemcitabine and irinotecan combinations appeared to have higher ORR, than older fluorouracil-based regimens. Some patients responded to more than one line of chemotherapy. Palliative chemotherapy predicted for overall survival (OS) in a multivariate analysis (HR 0.47, P = 0.035). CONCLUSION: Chemotherapy appears to have activity in adenocarcinoma of the small bowel. Prospective trials evaluating patient benefit are required to confirm this activity using newer systemic therapies, until such time retrospective reviews such as this will continue to guide treatment decisions.

Adenocarcinoma↗
PubMed2006

Genetic predisposition to colorectal cancer: new pieces in the pediatric puzzle.

Colorectal cancer is rare in childhood. The 2 best characterized familial syndromes, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) and familial adenomatous polyposis (FAP), are autosomal dominant inherited disorders. HNPCC is relevant to pediatric gastroenterology practice because children and adolescents with underlying colorectal cancer can have germ-line mutations of mismatch repair genes. Recent attention has focused on characterizing genetic predisposition to attenuated FAP in individuals who do not have germ-line mutations in the APC gene. The identification of a second mechanistic explanation called MYH-associated polyposis (MAP), which is an autosomal-recessive condition, has important implications for both screening and management strategies. Hereditary colorectal cancer including HNPCC, FAP, attenuated FAP and MYH-associated polyposis in children are the subject of this review.

Adenomatous Polyposis Coli↗
PubMed2006

Celecoxib treatment alters the gene expression profile of normal colonic mucosa.

A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-beta signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling.

Biomarkers↗
PubMed2006

Pancreatic cancer genetic epidemiology consortium.

We have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial pancreatic cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with pancreatic cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident pancreatic cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 (N = 72,700). The mean age +/- SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 +/- 11.8 and was 65.4 +/- 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 +/- 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all pancreatic cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in pancreatic cancer.

Age of Onset↗
PubMed2006

Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.

Previous case-control studies have suggested that carriers of monoallelic germline mutations in the MYH gene may be at increased risk of colorectal cancer. We applied a kin-cohort design, using a modified segregation analysis, to estimate the colorectal cancer risk using 300 first-degree relatives of 39 colorectal cancer cases who were monoallelic or biallelic carriers of MYH mutations. We found that monoallelic carriers had a 3-fold increased risk of colorectal cancer (hazard ratio, 2.9; 95% confidence interval, 1.2-7.0; P = 0.02) and biallelic carriers a 50-fold increased risk (hazard ratio, 53; 95% confidence interval, 14-200; P < 0.0001). This analysis illustrates the potential of family analysis to estimate cancer risk for low-frequency mutations and, based on the proportion of relatives predicted to be carriers, we believe that this constitutes the largest study of monoallelic carriers to date.

Adult↗