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Jeremy R Jass

Publications and source records attributed to Jeremy R Jass.

At least 37 records · Page 2Linked to original sources
PubMed2005

Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation.

PURPOSE: Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype. EXPERIMENTAL DESIGN: Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history. RESULTS: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer. CONCLUSIONS: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.

PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

CONTEXT: The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used. OBJECTIVE: To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing. RESULTS: Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone. CONCLUSIONS: The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer.

BACKGROUND AND AIMS: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. METHODS: A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. RESULTS: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) ( P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs ( P < .05). CONCLUSION: These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development.

Colorectal Neoplasms↗
PubMed2005

Serrated adenoma of the colorectum and the DNA-methylator phenotype.

Serrated adenomas (SA) of the colorectum show features intermediate between hyperplastic polyps (HP) and adenomas. HP and SA are related lesions and there is now strong evidence for a 'serrated-polyp pathway' to colorectal cancer (CRC) that is largely independent of the classic adenoma-to-carcinoma sequence. A recently recognized lesion in this pathway is a HP variant characterized by relatively large size, atypical histology and proximal location in the colorectum. This HP variant has been given a variety of names in the literature including 'sessile SA' and 'type I SA'. Because this lesion lacks the traditional cytology of colorectal adenoma and in order to avoid confusion with SA, it is referred to in this review as sessile serrated polyp. SA are characterized by a heterogeneous group of changes at the molecular level, but a high proportion have BRAFmutations and DNA methylation. They may develop in HP or sessile serrated polyps, or may arise de novo. In the serratedpolyp pathway, the advent of genetic instability is likely to be an important rate-limiting step that drives rapid neoplastic evolution. Methylation and inactivation of the DNA repair genes MLH1 and MGMT (O-6-methylguanine-DNA methyltransferase) have been proposed as critical steps leading to genetic instability. Stretches of DNA rich in the bases guanine and cytosine (CpG islands; where p represents a phosphodiester bond linking adjacent cytosine and guanine bases) that are normally unmethylated may become methylated in malignant human colorectal tumors. Subsets of colorectal cancers with an unusually high number of methylated CpG islands have been described as having the 'CpG-island-methylator phenotype' It is possible that many, if not all, CRCs with the CpG-island-methylator phenotype evolve through the serrated-polyp pathway that would, therefore, explain approximately 20% of all CRCs. The current lack of guidelines for managing serrated polyps may explain the static incidence of proximal CRC, despite the falling incidence rates for left-sided CRC during the same time period.

Adenoma↗
PubMed2005

The intestinal lesion of autistic spectrum disorder.

This editorial briefly reviews the significance of lymphoid nodular hyperplasia in the intestinal tract of children with autistic spectrum disorder. The distinction between physiological and pathological lymphoid hyperplasia of the intestinal tract is of importance in the context of a possible causative link with autism. A primary intestinal lesion may occur as part of the broad spectrum of immunological disorders to which autistic children are prone. This could result in increased intestinal permeability to peptides of dietary origin which may then lead to disruption of neuroregulatory mechanisms required for normal brain development. Alternatively, there could be a primary defect in the translocation and processing of factors derived from the intestinal lumen. These possibilities deserve further investigation and should not be lost in the fog of the controversy regarding the role of measles/mumps/rubella vaccination in the aetiology of autistic spectrum disorder.

Autistic Disorder↗
PubMed2005

Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept.

Serrated polyps of the large intestine, including traditional hyperplastic polyps, traditional serrated adenomas, and more recently described sessile serrated adenomas, have gained increased recognition in recent years because of growing evidence that one of these lesions, the sessile serrated adenoma, might be the precursor lesion for some cases of microsatellite unstable colorectal carcinoma. Nevertheless, there has been some reluctance to embrace the concept of sessile serrated adenoma, and numerous diagnostic challenges exist. This article, which grew out of the Roger C. Haggitt Gastrointestinal Pathology Society Forum presented in Vancouver, Canada, March 6, 2004 as part of the annual meeting of the United States-Canadian Academy of Pathology, reviews the morphologic and molecular evidence for the concept of various polyps in the general category of serrated polyps of the large intestine, in particular the lesion known as the sessile serrated adenoma, and provides a conceptual framework for diagnosis of these lesions.

Adenocarcinoma↗
PubMed2005

What's new in hereditary colorectal cancer?

Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation.

PURPOSE: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. PATIENTS AND METHODS: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16(INK4a), p14(ARF), COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. RESULTS: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. CONCLUSION: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

Aged↗
PubMed2004

Allelic loss of a common microsatellite marker MYCL1: a useful prognostic factor of poor outcomes in colorectal cancer.

PURPOSE: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly detected in colorectal cancer (CRC). The short arm of chromosome 1 is also frequently affected in a whole range of cancer types, including CRC. Our aim in the present study was to determine whether allelic losses on 1p were likely to be of much value in predicting the prognosis of CRC cases. EXPERIMENTAL DESIGN: Genomic DNA was prepared from tumor and corresponding normal tissue specimens from 90 patients who had undergone curative resection for CRC. Loss of heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was examined using 14 microsatellite markers, and possible correlations between LOH and clinicopathological factors (including tumor recurrence and patient survival) were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in 12 of 74 (16.2%) patients who were informative for this marker. RESULTS: After controlling for tumor stage and gender and excluding findings for patients with remote metastasis, we found that patients who were positive for LOH at MYCL1 were 31 times more likely to experience recurrence than those who were negative for LOH at this locus (95% confidence intervals, 2.27- infinity; P = 0.04). There were indications of a similar tendency for LOH at the 14-3-3-sigma-TG microsatellite marker at 1p35, but we could find no evidence of a significant association between LOH at this site and tumor recurrence or patient survival. We were also unable to detect significant association between LOH at the various sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient survival. CONCLUSIONS: CRC patients whose tumors exhibited LOH at MYCL1 at chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker may have clinical relevance.

Chromosome Mapping↗
PubMed2004

Role of inherited defects of MYH in the development of sporadic colorectal cancer.

Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been associated with multiple colorectal adenomas that display somatic G:C-->T:A transversions in APC. However, the effect of single germ-line variants has not been widely studied. To examine the relationship between monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC), 92 cases of sporadic CRC, 19 cases of familial CRC not meeting the Bethesda guidelines, 17 cases with multiple adenomas, and 53 normal blood donors were screened for 8 potentially pathogenic germ-line MYH variants. Loss of heterozygosity (LOH) at 1p adjacent to the MYH locus, microsatellite instability (MSI) status, and somatic mutations in KRAS2 and APC were analyzed in sporadic cancers. Neither homozygote nor compound heterozygote MYH variants were observed in the germ-line of any subjects with sporadic CRC. There was no difference in the incidence of monoallelic variants between this group (20 of 92, 22%) and cancer-free controls (14 of 53, 26%). However, the presence of monoallelic germ-line MYH variants was negatively associated with an MSI-high (MSI-H) tumor phenotype, with an incidence of only 1 of 23 (4%) MSI-H CRCs as contrasted with 19 of 69 (28%) non-MSI-H (P=0.02). Further, 4 of 5 tumors with 1p LOH contained monoallelic MYH variants compared with 15 of 53 without 1p LOH (P=0.04) and the normal population (P=0.03). The presence of G:C-->T:A transversions in KRAS2 or APC was significantly more common in single MYH variant tumors (9 of 12) than in MYH wild-type tumors (11 of 33; P=0.02). These results suggest that single germ-line variants of MYH may influence genetic pathways in CRC.

Adenoma↗
PubMed2004

Hyperplastic polyps and colorectal cancer: is there a link?

Most colorectal cancers (CRCs) are thought to arise in preexisting polyps called adenomas. A second type of colorectal polyp known as a hyperplastic polyp has been regarded as harmless for decades. Patients with hyperplastic polyps are therefore not thought to be at any increased risk of CRC, and best-practice guidelines indicate that these polyps do not require surveillance colonoscopy. Recently, it has become clear that CRC is not a single disease. One type of CRC (30%) shows a chemical alteration in DNA known as methylation, and a proportion of these also show genetic instability at the level of DNA. There is now strong evidence that the hyperplastic polyp is not harmless, but it might serve as the precursor of CRC with DNA methylation and deficient DNA mismatch repair. This novel pathway applies particularly to the subset of hyperplastic polyps that occurs in the proximal colon. If this premise is correct, it would be unsafe to ignore these polyps. There is now a need to define the genetic steps that explain the evolution of CRCs that develop within hyperplastic polyps. At the clinical level, it will be necessary to identify biomarkers for hyperplastic polyps that are especially prone to malignant conversion. Screening can then be targeted more selectively toward patients who are at significantly increased risk of malignant transformation of hyperplastic polyps.

Adenoma↗
PubMed2004

HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences.

Morphological features may serve as diagnostically useful markers of colorectal cancer (CRC) with the microsatellite instability-high (MSI-H) phenotype. The most important of these are lymphocytic infiltration, mucin secretion and poor differentiation. These features are apparent in both sporadic MSI-H CRC and CRC occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). There is now strong evidence that that the two principal subtypes of MSI-H CRC evolve through different pathways. Sporadic MSI-H CRC orginate within serrated polyps with BRAF mutation and DNA methylation while CRC in HNPCC arise within conventional adenomas in which there is frequent mutation of APC or beta -catenin and/or K- ras. These early differences in pathogenesis translate into multiple morphological distinctions in the cancers developing through the two pathways. Lymphocytic infiltration, tumour budding (de-differentiation), and co-existing adenomas are more evident in HNPCC while mucin secretion, poor differentiation, tumour heterogeneity and glandular serration, and co-existing serrated polyps are more evident in sporadic MSI-H CRC. Sporadic MSI-H CRC are also characterized by cytoplasmic eosinophilia and nuclei that are large, round, vesicular and contain a prominent nucleolus while in HNPCC the cytological features recapitulate the basophilia and nuclear characteristics of conventional adenomas. In practice, lymphocytic infiltration is the most sensitive marker of MSI-H status in both sporadic CRC and HNPCC. The crucial distinction between HNPCC and sporadic MSI-H CRC should be achieved by means of all available data including family history, age at onset of malignancy and molecular features. There is increasing evidence that genetic factors may predispose to DNA methylation. This can result in familial clustering of MSI-H CRC in which the underlying mechanism is methylation of hMLH1 rather than germline mutation. Morphological features can assist is distinguishing such families from bona fide HNPCC families which they closely mimic.

Adult↗
PubMed2004

A new prognostic staging system for rectal cancer.

OBJECTIVE: To clarify the appropriateness of tumor "budding," a quantifiable histologic variable, as 1 parameter in the construction of a new prognostic grading system for rectal cancer. SUMMARY BACKGROUND DATA: Patient division according to an accurate prognostic prediction could enhance the effectiveness of postoperative adjuvant therapy and follow-up. PATIENTS AND METHODS: Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than 5 cells in the invasive frontal region, and was divided into 2 grades based on its number within a microscopic field of x250. We analyzed 2 discrete cohorts comprising 638 and 476 patients undergoing potentially curative surgery. RESULTS: In the first cohort, high-grade budding (10 or more foci in a field) was observed in 30% of patients and was significantly associated with a lower 5-year survival rate (41%) than low-grade budding (84%). Similarly, in the second cohort, the 5-year survival rate was 43% in high-grade budding patients and 83% in low-grade budding patients. In both cohorts, multivariate analyses verified budding to be an independent prognosticator, together with nodal involvement and extramural spread. These 3 variables were given weighted scores, and the score range was divided to provide 5 prognostic groups (97%; 86%; 61%; 39%; 17% 5-year survival). The model was tested on the second cohort, and similar prognostic results were obtained. CONCLUSIONS: We propose that because of its relevance to prognosis and its reproducibility, budding is an excellent parameter for use in a grading system to provide a confident prediction of clinical outcome.

Adenocarcinoma↗
PubMed2004

Role of the pathologist in the diagnosis of hereditary non-polyposis colorectal cancer.

The aim of this paper is to indicate how the pathologist may suspect a diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) on the basis of histological criteria and patient age alone. A single morphological feature, namely the presence of intra-epithelial lymphocytes (tumor infiltrating lymphocytes), identifies the majority of colorectal cancers (CRC) with the DNA microsatellite instability-high phenotype. A number of pathological criteria can help to distinguish HNPCC from sporadic MSI-H CRC, though age below 60 years is an important pointer towards HNPCC. Immunohistochemistry to demonstrate loss of expression of DNA mismatch repair genes serves as a highly reliable test of mismatch repair deficiency if antibodies to hMLH1, hMSH2, hMSH6 and hPMS2 are employed.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases.

PURPOSE: Because O(6)-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. EXPERIMENTAL DESIGN: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. RESULTS: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). CONCLUSIONS: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.

Aged↗