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J R Jass

Publications and source records attributed to J R Jass.

At least 55 records · Page 3Linked to original sources
PubMed2001

Molecular and cellular biology of pre-malignancy in the gastrointestinal tract.

Important pathogenic alterations within established cancers are acquired during the pre-malignant stage. These genetic alterations can be grouped into specific neoplastic pathways that differ within and between anatomical sites. By understanding the mechanisms that determine the initiation and progression of each pathway, it will be possible to develop novel approaches to the diagnosis, prevention and treatment of cancer. This chapter outlines the principles underlying the molecular characterization of pre-malignant lesions, taking colorectal neoplasia as the main model.

Colonic Polyps↗
PubMed2001

Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status.

BACKGROUND: The presence of high level DNA microsatellite instability (MSI-H) in colorectal cancer is associated with an improved prognosis, as is the presence of tumour infiltrating lymphocytes (TILs). It is not clear if TILs contribute directly to the survival advantage associated with MSI-H cancers through activation of an antitumour immune response. AIMS: To correlate TIL and apoptosis rates in colorectal cancer stratified by MSI status. METHODS: The distribution of TILs was characterised and quantified in a selected series of 102 sporadic colorectal cancers classified according to levels of MSI as 32 MSI-H, 30 MSI-low (MSI-L), and 40 microsatellite stable (MSS). Archival blocks were immunostained using the T cell markers CD3 and CD8, and the B cell marker CD20. Apoptosis of malignant epithelial cells was quantified by immunohistochemistry with the M30 CytoDEATH antibody. RESULTS: Positive staining with anti-CD3 and negative staining with anti-CD20 identified virtually all TILs as T cells. The majority of CD3+ TILs (>75%) also stained with anti-CD8. TILs were most abundant in MSI-H colorectal cancers in which 23/32 (72%) scored as TIL positive. Only 5/40 (12.5%) MSS tumours and 9/30 (30%) MSI-L cancers were TIL positive (p<0.0001). MSI-H cancers showed a twofold higher rate of apoptosis (mean (SD) 3.52 (0.34)%) than the MSS cancers (1.53 (0.23)%) while the MSI-L subgroup had an intermediate level (2.52 (0.35)%) (p<0.0001). Overall, there was a small (r=0.347) but significant linear correlation between CD3+ and M30+ random apoptosis counts (p<0.001). However, TILs and apoptosis showed little colocalisation. CONCLUSIONS: While TILs might be expected to explain the increased apoptotic rate and improved prognosis of MSI-H cancers, it is likely that TILs and apoptosis are independent characteristics of MSI-H cancers.

Adenocarcinoma↗
PubMed2001

Proliferation, apoptosis, and survival in high-level microsatellite instability sporadic colorectal cancer.

Sporadic colorectal cancer (CRC) characterized by high-level DNA microsatellite instability (MSI-H) has a favorable prognosis. The reason for this MSI-H survival advantage is not known. The aim of this study was to correlate proliferation, apoptosis, and prognosis in CRC stratified by MSI status. The proliferative index (PI) was measured by immunohistochemical staining with the Ki-67 antibody in a selected series of 100 sporadic colorectal cancers classified according to the level of MSI as 31 MSI-H, 29 MSI-Low (MSI-L), and 40 microsatellite stable (MSS). The Ki-67 index was significantly higher in MSI-H cancers (P < 0.0001) in which the PI was 90.1 +/- 1.2% (mean +/- SE) compared with 69.5 +/- 3.1% and 69.5 +/- 2.3% in MSI-L and MSS subgroups, respectively. There was a positive linear correlation between the apoptotic index (AI) and PI (r = 0.51; P < 0.001), with MSI-H cancers demonstrating an increased AI:PI ratio indicative of a lower index of cell production. A high PI showed a trend toward predicting improved survival within MSI-H cancers (P = 0.09) but did not predict survival in MSI-L or MSS cancers. The AI was not associated with survival in any MSI subgroup. In conclusion, this is the first study to show that sporadic MSI-H cancers are characterized by a higher AI:PI ratio and increased proliferative activity compared with MSI-L and MSS cancers, and that an elevated PI may confer a survival advantage within the MSI-H subset.

Aged↗
PubMed2000

p73 is up-regulated in a subset of hepatocellular carcinomas.

Loss of heterozygosity (LOH) at 1p36 occurs in a number of solid tumors including hepatocellular carcinoma (HCC). Recently, a novel gene, p73, has been identified at 1p36.33. p73 is structurally and functionally related to p53 located at 17p13.1, which is a target for inactivation in HCCs. p73 produces at least two splicing variants, p73alpha and beta, and a polymorphism in exon 2 results in two alleles, GC or AT. Initially, only the AT allele and p73alpha transcripts were identified in malignant cell lines, suggesting a role for these in the malignant phenotype. The aims of this study were to determine the extent of LOH at 1p36 and 17p13.1 in HCCs from Australia and South Africa, and to identify patterns of p73 mRNA and p73 and p53 protein expression. LOH at 1p36 was found in 8 of 25 Australian and 6 of 10 South African cases. p73 mRNA expression occurred in 8 HCCs, but not in nonmalignant liver tissue. Two of these 8 HCCs had LOH of 1p36. Both alpha and beta transcripts were observed in GC/GC homozygotes and GC/AT heterozygotes. No p73 protein expression was observed by immunohistochemistry in nonmalignant liver tissue or in HCC. p53 inactivation appeared to be associated with up-regulation of p73 expression, suggesting a compensatory role for p73 in this situation. The LOH at 1p36 implies a liver-specific tumor suppressor gene is in this region. However, the up-regulation of p73 mRNA suggests p73 is not the target of this loss.

Adult↗
PubMed2000

Histopathology of early colorectal cancer.

The histopathologic spectrum of early colorectal cancer (ECC) is compared from the Western and Japanese perspective. In the West, most ECC presents as a malignant adenoma, whereas superficial ECC with no adenomatous component is well described in the Japanese literature. Furthermore, superficial ECC is thought to progress rapidly and disseminate early. The discrepant viewpoints are considered in the light of different approaches to histopathologic interpretation. Lesions reported by Japanese pathologists as superficial carcinomas limited to the mucosa are diagnosed as flat adenomas in the West. In one Japanese series only 4 of 218 (1.8%) flat or small sessile neoplasms removed by endoscopic mucosal resection were associated with submucosal invasion by carcinoma. Therefore superficial ECC with submucosal spread is uncommon. Most ECC in hereditary nonpolyposis colorectal cancer evolves through the adenoma-carcinoma pathway (including flat adenoma). However, adenoma removal in the context of population-based screening programs has not lowered the incidence of colorectal cancer; flat colorectal neoplasia may be important in clinical practice.

Adenocarcinoma↗
PubMed2000

Familial colorectal cancer: pathology and molecular characteristics.

Appropriate management of familial colorectal cancer revolves around the diagnosis of the underlying genetic syndrome. This necessitates an interdisciplinary approach allowing integration of clinical, morphological, and molecular evidence that may involve several members of the same family. Genetic disorders express themselves over time, whereas clinical investigation of family members is likely to be episodic. Generic features of hereditary colorectal cancer syndromes include a positive family history, early age at onset, multiple neoplasms, and extracolonic lesions of either a developmental or neoplastic nature. Deriving a complete description of a genetic disorder is hampered by the need to trace and obtain tissue samples from many institutions. This review examines the usefulness of tissue-based investigations, both morphological and molecular, in raising the suspicion of familial colorectal cancer, providing a definitive tissue diagnosis and contributing to the larger body of diagnostic evidence. The account focuses on the two most well-studied syndromes--familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC)--but consideration is also given to less well-understood syndromes. Some of these, notably hyperplastic polyposis and mixed polyposis, may closely mimic FAP or HNPCC.

Adenomatous Polyposis Coli↗
PubMed2000

Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer.

BACKGROUND: Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behaviour. This study analyses the association between extensive MSI (MSI-H), clinicopathological features and survival in an unselected group of patients with sporadic Australian Clinico-Pathological Stage (ACPS) C (tumour node metastasis stage III) colorectal cancer. METHODS: Some 255 patients who underwent resection for sporadic ACPS C colorectal cancer between 1986 and 1992 were studied. No patient had received chemotherapy. Minimum follow-up for all patients was 5 years. Archival normal and tumour DNA was extracted and amplified by polymerase chain reaction using a radioactive labelling technique. MSI-H was defined as instability in 40 per cent or more of seven markers. RESULTS: Twenty-one patients showed MSI-H. No association was found between MSI and age or sex. Tumours exhibiting MSI-H were more commonly right sided (P<0.00001), larger (P = 0.002) and more likely to be high grade (P = 0.049). After adjustment for age, sex and other pathological variables, patients whose cancers exhibited MSI-H had improved survival (P = 0.015). CONCLUSION: Recognition of MSI-H in sporadic ACPS C tumours identifies a subset of cancers with improved prognosis. Such stratification should be considered in trials of adjuvant therapy and may be relevant to therapeutic decision making.

Adult↗
PubMed2000

Adenocarcinoma of colon differentiating as dome epithelium of gut-associated lymphoid tissue.

AIMS: An early adenocarcinoma of the ascending colon was confined to a mass of gut-associated lymphoid tissue (GALT). The first description of an adenocarcinoma of colon differentiating as dome epithelium is presented. METHODS AND RESULTS: A plaque-like carcinoma was identified opposite the ileocaecal valve in an asymptomatic 56-year-old man with a family history of colorectal cancer. Malignant epithelium was confined to a mass of GALT filling but limited to the submucosa. Characterization of the neoplasm was undertaken by means of mucin histochemistry, immunohistochemistry, electron microscopy and assessment of DNA microsatellite instability status. The malignant epithelium comprised well differentiated columnar cells with a microvillous brush border and expressing MUC1, but no goblet cells or expression of MUC2. The demonstration of focal clusters of intraepithelial B-lymphocytes supported the presence of functioning M-cells within the malignant neoplasm. The cancer was DNA microsatellite stable despite the finding of tumour infiltrating lymphocytes. CONCLUSIONS: There is evidence for the origin of colorectal neoplasia from dome epithelium in both experimental models and microreconstruction studies of early adenomas in nonpolypotic human colorectal mucosa. It is suggested that the lymphocyte-rich subset of colorectal cancer that expresses MUC1 but not MUC2 may be differentiating as dome epithelium of gut-associated lymphoid tissue.

Adenocarcinoma↗
PubMed2000

Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum.

Although the scientific and clinical rationale for classifying colorectal cancer according to mechanisms underlying genetic instability is well supported, little is known of the early morphogenesis of sporadic cancer showing high levels of DNA microsatellite instability (MSI-H). Evidence is accumulating that the traditional adenoma-carcinoma sequence may not apply to sporadic MSI-H colorectal cancer. The serrated pathway comprising hyperplastic polyps, mixed polyps and serrated adenomas may serve as the missing link. This review relates the recently described CpG island methylator phenotype (CIMP) to the serrated pathway. Two rate-limiting genetic steps may underlie the neoplastic pathway associated with CIMP. A transmembrane receptor expressed by pericryptal myofibroblasts (HPP1) may be implicated in the transition from normal to hyperplasia whereas inactivation of hMLH1 is responsible for the conversion of hyperplasia to dysplasia through loss of DNA mismatch repair. These mechanisms fit with clinical observations relating to sporadic MSI-H colorectal cancer, specifically proximal location, multiplicity, higher frequency among females and rapid evolution of early cancer.

Colonic Neoplasms↗
PubMed2000

Pathology of hereditary nonpolyposis colorectal cancer.

The magnitude of the pathologist's role in the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) is underestimated. The diagnostic features are not specific to HNPCC cancers, but relate to all cancers showing high levels of DNA microsatellite instability (MSI-H). Three major groups of MSI-H cancers can be recognized by histopathological criteria: (1) right-sided poorly differentiated cancers, (2) right-sided mucinous cancers, and (3) adenocarcinomas in any location showing tumor-infiltrating (intraepithelial) lymphocytes (TIL). The poorly differentiated cancers are relatively well circumscribed and the cells are arranged in sheets or trabeculae. TIL may be very numerous in poorly differentiated cancers. The presence of TIL as estimated in H&E sections equates with a percentage of intraepithelial T cells (CD3+) in the range of 4 to 30%. Most of the T cells are CD8+ (cytotoxic T cells). Peritumoral lymphocytes and the so-called Crohn's-like reaction are associated with TIL, but are harder to quantify. Of the 15% of colorectal cancers that are MSI-H, 13% will be sporadic and 2% will occur in the context of HNPCC. HNPCC should be suspected if the patient is young (less than 55 years) because sporadic MSI-H cancers (associated with hypermethylation of the promoter region of hMLH1) occur almost exclusively in elderly subjects. Workup of a suspected case should include DNA microsatellite testing with a panel of mononucleotide (e.g., BAT26, BAT25) and dinucleotide (e.g., D5S346, D2S123, and D177S250) markers before referral to a cancer family or clinical genetics clinic. Immunohistochemical staining for hMLH1 and hMSH2 identifies the underlying mutation in a proportion of cases. The colorectal adenoma is the usual precursor lesion in HNPCC, though serrated polyps are implicated in a small subset.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2000

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer.

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.

Adenoma↗