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Jeremy R Jass

Publications and source records attributed to Jeremy R Jass.

At least 19 recordsLinked to original sources
PubMed2007

Differential significance of tumour infiltrating lymphocytes in sporadic mismatch repair deficient versus proficient colorectal cancers: a potential role for dysregulation of the transforming growth factor-beta pathway.

The prognostic importance of tumour infiltrating lymphocytes (TILs) in colorectal cancer (CRC) remains controversial. The present study was undertaken to evaluate the role of TILs as prognostic indicators and to investigate the role of transforming growth factor-beta (TGF-beta) in TIL infiltration. Immunohistochemical staining for components in the TGF-beta pathway was performed on a tissue microarray of 1420 unselected CRCs with complete clinico-pathological data. Statistical analyses were carried out on samples stratified by mismatch repair (MMR) proficiency status and TIL counts. TIL infiltration was found to correlate with multiple clinico-pathological features but was a prognostic marker only in MMR proficient CRCs. In all CRCs, findings indicative of insensitivity to TGF-beta and increased TGF-beta secretion were independent predictors of high TIL counts, suggesting that perturbations in the TGF-beta signalling pathway play an important role in the recruitment and retention of TILs within CRC epithelium.

Colorectal Neoplasms↗
PubMed2006

Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer.

BACKGROUND: Cut-off scores for determining positivity of biomarkers detected by immunohistochemistry are often set arbitrarily and vary between reports. AIMS: To evaluate the performance of receiver operating characteristic (ROC) curve analysis in determining clinically important cut-off scores for a novel tumour marker, the receptor for hyaluronic acid mediated motility (RHAMM), and show the reproducibility of the selected cut-off scores in 1197 mismatch-repair (MMR) proficient colorectal cancers (CRC). METHODS: Immunohistochemistry for RHAMM was performed using a tissue microarray of 1197 MMR-proficient CRC. Immunoreactivity was scored using a semi-quantitative scoring method by evaluating the percentage of positive tumour cells. ROC curve analysis was performed for T stage, N stage, tumour grade, vascular invasion and survival. The score with the shortest distance from the curve to the point with both maximum sensitivity and specificity, i.e. the point (0.0, 1.0), was selected as the cut-off score leading to the greatest number of tumours correctly classified as having or not having the clinical outcome. In order to determine the reliability of the selected cut-off scores, 100 bootstrapped replications were performed to resample the data. RESULTS: The cut-off score for T stage, N stage, tumour grade and vascular invasion was 100% and that for survival 90%. The most frequently selected cut-off score from the 100 resamples was also 100% for T stage, N stage, tumour grade, and vascular invasion and 90% for survival. CONCLUSIONS: ROC curve analysis can be used as an alternative method in the selection and validation of cut-off scores for determining the clinically relevant threshold for immunohistochemical tumour positivity.

Biomarkers, Tumor↗
PubMed2006

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis.

Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O(6)-methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer.

Adolescent↗
PubMed2006

SnoN expression is differently regulated in microsatellite unstable compared with microsatellite stable colorectal cancers.

BACKGROUND: SnoN is an important regulator of the transforming growth factor beta (TGFbeta) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity. METHODS: To further explore the role of this complex molecule in colorectal tumorigenesis, we examined 52 paired normal and tumour colorectal specimens stratified by level of microsatellite instability; 18 with high-level microsatellite instability (MSI-H) and 34 microsatellite stable (MSS). SnoN transcript expression was quantitated by real-time PCR and analysed with respect to clinical indicators of prognosis. RESULTS: Within the MSI-H subgroup, SnoN was commonly either up-regulated (6/18, 33%) or down-regulated (7/18, 39%). A significantly different distribution of SnoN expression was observed in MSS cancers compared with MSI-H (P < or = 0.001). Whilst 17/34 (50%) of MSS tumours demonstrated up-regulation, none showed down-regulated expression. Within the MSI-H subgroup, up-regulation was significantly correlated with lack of repeat tract mutation in the TGFbetaRII gene (P < or = 0.025), suggesting that SnoN is more frequently up-regulated in the presence of functional TGFbeta signalling. CONCLUSION: Together these data support the notion that SnoN has both oncogenic and tumour suppressive properties depending on other genetic changes within the tumour, and that the MSI-H pathway of colorectal tumorigenesis presents an excellent model for the study of these opposing functions.

Colorectal Neoplasms↗
PubMed2006

Hereditary Non-Polyposis Colorectal Cancer: the rise and fall of a confusing term.

The term Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example the Amsterdam criteria. It is now apparent that not all Amsterdam criteria-positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsatellite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair (MMR) gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. Families with a strong family history of colorectal cancer that do not have Lynch syndrome have been grouped as 'Familial Colorectal Cancer Type-X'. The first step in characterizing these cancer families is to distinguish them from Lynch syndrome. The term HNPCC no longer serves any useful purpose and should be phased out.

Alleles↗
PubMed2006

High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.

BACKGROUND & AIMS: Sporadic colorectal cancers with a high degree of microsatellite instability are a clinically distinct subgroup with a high incidence of BRAF mutation and are widely considered to develop from serrated polyps. Previous studies of serrated polyps have been highly selected and largely retrospective. This prospective study examined the prevalence of sessile serrated adenomas and determined the incidence of BRAF and K-ras mutations in different types of polyps. METHODS: An unselected consecutive series of 190 patients underwent magnifying chromoendoscopy. Polyp location, size, and histologic classification were recorded. All polyps were screened for BRAF V600E and K-ras codon 12 and 13 mutations. RESULTS: Polyps were detected in 72% of patients. Most (60%) were adenomas (tubular adenomas, tubulovillous adenomas), followed by hyperplastic polyps (29%), sessile serrated adenomas (SSAs; 9%), traditional serrated adenomas (0.7%), and mixed polyps (1.7%). Adenomas were more prevalent in the proximal colon (73%), as were SSAs (75%), which tended to be large (64% >5 mm). The presence of at least one SSA was associated with increased polyp burden (5.0 vs 2.5; P < .0001) and female sex (P < .05). BRAF mutation was rare in adenomas (1/248 [0.4%]) but common in SSAs (78%), traditional serrated adenomas (66%), mixed polyps (57%), and microvesicular hyperplastic polyps (70%). K-ras mutations were significantly associated with goblet cell hyperplastic polyps and tubulovillous adenomas (P < .001). CONCLUSIONS: The prevalence of SSAs is approximately 9% in patients undergoing colonoscopy. They are associated with BRAF mutation, proximal location, female sex, and presence of multiple polyps. These findings emphasize the importance of identifying and removing these lesions for endoscopic prevention of colorectal cancer.

Adenoma↗
PubMed2006

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer.

RHAMM, a member of the microtubule-associated protein family that interacts with the mitogen-activated protein kinase pathway, is associated with tumor progression, aggressive disease and shortened survival in several tumor types. This study aimed to determine the prognostic value of RHAMM in colorectal cancer (CRC). A series of 1420 unselected, nonconsecutive CRC resections were subdivided into three groups: (1) DNA mismatch repair (MMR)-proficient, (2) MLH1 negative and (3) presumed Lynch syndrome. Immunohistochemical analysis of RHAMM expression (0 vs >0%), increasing expression (increasing percentage positivity) and complete expression (100 vs <100%) was performed using tissue microarray technique and the results were correlated with clinicopathological parameters. Fifty-seven tissue samples of normal colonic mucosa were included as a control group. In a univariate analysis increasing and complete expression of RHAMM were associated with higher N stage (P=0.023 and 0.021) and worse survival (P<0.0001) in MMR-proficient CRC. Complete expression of RHAMM was associated with worse survival in presumed Lynch syndrome (P=0.016). In MLH1-negative CRC there was no association between RHAMM expression and the clinicopathological features. In a multivariate analysis, increasing RHAMM expression was an independent adverse prognostic factor in MMR-proficient CRC (P<0.0001) and complete expression in MMR-proficient CRC and presumed Lynch syndrome (P<0.0001 and P=0.031, respectively). Nuclear pERK expression was associated with increasing RHAMM expression in MMR-proficient CRC (P=0.012) and with complete RHAMM expression in presumed HNPCC (P=0.03). Increasing and complete RHAMM expressions are independent adverse prognostic factors in MMR-proficient CRC and presumed Lynch syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer.

Molecular tumor markers are often studied in colorectal cancer using immunohistochemistry to determine their prognostic or predictive value. Protein expression is typically assigned a 'positive' score based on a predetermined cutoff. A semiquantitative scoring method that evaluates the percentage of positive tumor cells (0-100%) may provide a better understanding of the prognostic or predictive significance of these markers. The aim of this study was to assess and compare the interobserver agreement of immunohistochemistry scores using a percentage scoring method and three categorical scoring systems. Immunohistochemistry for p53, Bcl-2, vascular endothelial growth factor (VEGF) and apoptotic protease activating factor-1 (APAF-1) was performed on 87 tumor biopsies from patients with rectal carcinoma and scored independently by four pathologists as the percentage of positive tumor cells. Interobserver agreement was assessed by the intraclass correlation coefficient. The intraclass correlation coefficients for p53 and VEGF (>0.6) indicate substantial agreement between observers. The distribution of Bcl-2 and APAF-1 scores in addition to weaker interobserver agreement by percentage scoring suggest that this approach may not be appropriate for these proteins. In conclusion, p53 and VEGF protein expression assessed by immunohistochemistry in colorectal cancer and scored as a percentage of positive tumor cells may be a viable alternative scoring method.

Adenocarcinoma↗
PubMed2006

Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal-regulated kinase, and phosphorylated AKT in colorectal cancer-a tissue microarray-based approach.

Tumor budding is defined as dedifferentiated cancer cells at the invasive margin of colorectal cancer (CRC) and correlates with a worse prognosis. The invasive margin and tumor budding are normally not present in a superficial diagnostic biopsy specimen. The aim of this study was to investigate the expression/overexpression of 2 downstream molecules of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways, phosphorylated AKT (pAKT) and phosphorylated extracellular signal-regulated kinase (pERK), in areas of CRC away from the invasive margin and determining if these variables were predictive of tumor budding or prognosis. A series of 1420 unselected, nonconsecutive CRC resections were subdivided into 3 groups: (1) DNA mismatch repair (MMR) proficient, (2) MLH1-negative, and (3) presumed HNPCC. Immunohistochemical analysis of pAKT and pERK expression (0% versus > 0%) and overexpression (increasing percentage of positivity) was performed using the tissue microarray technique. The results were correlated with clinicopathologic parameters. Fifty-seven samples of normal colon mucosa were included as a control group. Nuclear pERK expression (P = .008) was associated with presence of tumor budding in the MMR-proficient, but not in the MLH1-negative and presumed-HNPCC groups. In contrast, cytoplasmic pAKT overexpression was associated with early T stage (P = .04), early N stage (P = .02), and absence of tumor budding (P = .03) only in the MLH1-negative group. There was no association between pERK or pAKT and clinicopathologic parameters in the HNPCC group. Dysregulation of the mitogen-activated protein kinase pathway is likely to be implicated in the mechanism of tumor budding only in MMR-proficient CRC, whereas the phosphoinositide 3-kinase/AKT pathway is associated with early stage in MLH1-negative CRC.

Adenocarcinoma↗
PubMed2006

DNA methylation patterns in adenomas from FAP, multiple adenoma and sporadic colorectal carcinoma patients.

Colorectal adenomas have traditionally been regarded as homogeneous. The aim of our study was to identify molecular features that may differentiate sporadic adenomas from familial adenomas such as Familial Adenomatous Polyposis (FAP) and Multiple Adenoma patients. DNA methylation was tested at Methylated IN Tumor (MINT) loci (1,2,12,31) and the CpG promoter region of genes MLH1, HPP1, MGMT, p14ARF and p16INK4a in FAP-associated adenomas (33) from 5 patients with a known APC mutation (Group 1, FAP), adenomas (29) from 4 Multiple Adenoma patients (Group 2 Multiple), adenomas (14) from 3 patients with sporadic colorectal cancers showing high microsatellite instability (Group 3, MSI-H) and adenomas (16) from 7 patients, with sporadic colorectal cancers showing microsatellite stable or low level instability (Group 4, MSS/MSI-L). Aberrant Crypt Foci (ACFs), Hyperplastic Polyps (HPs) and cancers were also examined for methylation status as well as K-ras mutation. Multiple Adenoma patients were examined for germline polymorphisms in the base excision repair gene, MYH. The familial syndrome, FAP -associated adenomas showed a significantly low frequency of MINT methylation (15.5%,) compared to sporadic MSS/MSI-L-associated adenomas (35.5%). Group 3 (MSI-H) adenomas were different in that many showed serration and a high level of methylation (57.1%). Group 2, Multiple Adenoma cases, resembled sporadic MSS/MSI-L-associated adenomas. However the promoter regions of key genes, MGMT, p14ARF and p16INK4a were methylated to a greater extent than MINTs in both sporadic and familial adenomas. Genetic profiling of adenomas supports the concept that adenomas belonging to familial syndromes pursue a different pathway to tumorigenesis than their sporadic counterpar/ts from their earliest formation.

Adenoma↗
PubMed2006

Tumor buds show reduced expression of laminin-5 gamma 2 chain in DNA mismatch repair deficient colorectal cancer.

PURPOSE: Tumor budding at the invasive margin of colorectal cancer is an important adverse prognostic factor. The subset of colorectal cancer that is deficient in DNA mismatch repair has been associated with a good prognosis. It is hypothesized that tumor budding in this subset may lack biologic aggressiveness because it is not associated with aberrant expression of the independent prognostic factor, laminin-5 gamma 2. METHODS: Eighty colorectal cancers with high-grade tumor budding were studied, including nine sporadic colorectal cancers with immunohistochemical loss of expression of MLH1 (MLH1(-)), seven colorectal cancers from patients with hereditary nonpolyposis colorectal cancer, and 64 sporadic colorectal cancers expressing both MLH1 and MSH2 (MLH1(+)). Two regulatory mechanisms for laminin-5 gamma 2 expression were explored, including aberrant nuclear expression of beta-catenin by immunohistochemistry and promoter methylation of laminin-5 gamma 2 by methylation-specific polymerase chain reaction. RESULTS: Only three of nine MLH1(-) colorectal cancers showed expression of laminin-5 gamma 2 compared with 46 of 64 MLH1(+) colorectal cancers (P = 0.05). Only two of seven hereditary nonpolyposis colorectal cancers expressed laminin-5 gamma 2 compared with MLH1(+) colorectal cancers (P= 0.03). Expression of nuclear beta-catenin was more frequent (58 percent) in MLH1(+) colorectal cancers compared with MLH1(-) colorectal cancers (11 percent, P = 0.01). Methylation of laminin-5 gamma 2 was found in 5 of 38 (13 percent) cases but did not differ among colorectal cancer subsets. Four of five colorectal cancers with methylation of laminin-5 gamma 2 were scored as negative for laminin-5 gamma 2 by immunohistochemistry. CONCLUSIONS: The reduced expression of laminin-5 gamma 2 in colorectal cancers with deficient DNA mismatch repair may underlie a variant of tumor budding that is relatively nonaggressive.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia.

PURPOSE: In colorectal cancer, the presence of cytoplasmic podia around tumor budding foci may be a morphologic marker for an activated budding phenotype that is associated with cell motility. In this study, we have investigated the prognostic significance of cytoplasmic podia. METHODS: A total of 136 pT3 colorectal cancers were classified according to extent of budding and cytoplasmic podia as identified by immunostaining for cytokeratin. The prognostic significance of budding and cytoplasmic podia was then assessed. RESULTS: The overall survival curves between the groups with high-grade and low-grade cytoplasmic podia were different (5-year survival rates were 60.5 and 83.8 percent respectively, P = 0.0003). Similar results were shown for tumor budding (59.8 and 87.7 percent, P < 0.0001). Multivariate analysis showed that the grades of cytoplasmic podia (hazards ratio, 2.4; P = 0.012) and budding (hazards ratio, 2.3; P = 0.024) were independent prognostic factors. Additionally, among colorectal cancers with high-grade budding, the grade of cytoplasmic podia was selected as an independent prognostic factor (hazards ratio, 2.4; P = 0.042). CONCLUSIONS: Cytoplasmic podia and budding are related but independent pathologic predictive markers in patients with resected pT3 colorectal cancer.

Aged↗
PubMed2006

Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study.

BACKGROUND & AIMS: Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history. METHODS: Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier. RESULTS: Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%-62%) for men and 38% (19%-51%) for women. Corresponding risks were 67% (47%-84%) and 72% (48%-85%) for any hereditary nonpolyposis colorectal cancer-related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter. CONCLUSIONS: For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Postchemotherapy characteristics of hepatic colorectal metastases: remnants of uncertain malignant potential.

Accepted management for colorectal cancer (CRC) involves resection of the primary neoplasm and chemotherapy; the debate continues over the most beneficial order of these components. Preoperative chemotherapy aimed at liver metastases may result in complete pathologic response and replacement of the malignancy with scar. The McGill University liver diseases database was retrospectively reviewed. Forty-one patients receiving treatment between December 2003 and August 2004 were identified, their medical records examined, and liver histology reviewed. The histology of the remnants was linked to the appearance of the lesions on preresection imaging and to the primary colorectal neoplasms. Twenty-seven of the 41 patients (66%) received preoperative chemotherapy (oxaliplatin or irinotecan). Features of the primary neoplasm that predicted resolution of the metastases were absence of tumor budding (P = 0.04), absence of a diffusely infiltrative tumor margin (P = 0.02), and loss of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase (P = 0.08). Oxaliplatin and irinotecan demonstrate beneficial effects in treating hepatic colorectal metastases and should be considered in such patients before resection. We propose the acronym RUMP to denote the remnants of uncertain malignant potential remaining. Further investigation is required to determine any correlation between the drug received and the resulting lesion.

Adult↗
PubMed2006

Hyperplastic polyposis and cancer of the colon with gastrinoma of the duodenum.

BACKGROUND: A 64-year-old woman presented to the emergency room with a 3-month history of intermittent abdominal cramps, accompanied by nausea, vomiting, anorexia, and decreased bowel movements consistent with a partial intestinal obstruction. She had a 12-year history of peptic ulcers, which had been treated with histamine-2 blockers. INVESTIGATIONS: Physical examination, abdominal X-ray, abdominal CT scan, colonoscopy and assessment of gastrin levels. DIAGNOSIS: Duodenal neuroendocrine neoplasm showing gastrin expression and stage III (T3N2M0), poorly differentiated adenocarcinoma of the cecum arising from hyperplastic polyposis. MANAGEMENT: Right-sided hemicolectomy with ileocolonic anastomosis, duodenal resection, leucovorin and 5-fluorouracil chemotherapy, annual colonoscopic surveillance, and polypectomy.

Adenocarcinoma↗
PubMed2006

The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature.

In recent years, an alternative pathway of colorectal cancer development has been described in which serrated polyps replace the traditional adenoma as the precursor lesion. Importantly, serrated polyps and a subset of colorectal cancer show largely nonoverlapping mutation profiles to those found in adenomas and the majority of colorectal cancer. These genetic alterations include activating mutation of the BRAF proto-oncogene and widespread gene promoter hypermethylation (CpG island methylator phenotype or CIMP). Up to 15% of colorectal cancer is likely to develop on the basis of a strong genetic predisposition. The two most well-characterized syndromes, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome), both develop via the adenoma-carcinoma pathway and together account for approximately one third of familial colorectal cancer. We have recently described 11 families in which there is evidence that the genetic predisposition to autosomal dominant colorectal cancer is linked to the serrated pathway. This condition, serrated pathway syndrome, and the related condition, hyperplastic polyposis, the presentation of which suggests a recessive mode of inheritance, represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. Further, CIMP is observed in the normal colonic mucosa of individuals with hyperplastic polyposis consistent with a field defect in epigenetic regulation. The spectrum of serrated neoplasia may also implicate the apparently sporadic and later onset subset of colorectal cancer with high levels of microsatellite instability. The tendency for these lesions to be multiple, associated with smoking, and to show frequent BRAF mutation and CIMP points to a defect that may result from interactions between the environment and a weakly penetrant genetic alteration.

Adenocarcinoma↗