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.

Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity.

Although microsatellite instability (MSI) has been shown to be present in 15% of sporadic colorectal carcinomas, the genetic events underlying the development of these tumors have not been well described. By investigating intratumoral heterogeneity, this study attempts to elucidate whether MSI-positive colorectal carcinomas develop as the result of a random accumulation of mutations or as an ordered, stepwise sequence of genetic alterations. Eighty-six regions from 16 MSI-positive sporadic colorectal carcinomas were examined for mutations in repeat nucleotide sequences of the tumour suppressor genes transforming growth factor beta type II receptor (TGFBRII), insulin-like growth factor II receptor (IGFIIR), and BAX, and the mismatch repair genes MSH3 and MSH6.

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).

Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum.

Aim: Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6.

Materials And Methods: The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers.

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.

Distribution and stability of membrane proteins in lipid membranes on solid supports.

Bacteriorhodopsin and the nicotinic acetylcholine receptor were biotinylated and reconstituted in lipidic membranes on silicon supports by fusion with proteoliposomes. The presence and distribution of the proteins were studied by binding with streptavidin. Radio-labelled streptavidin was employed for quantifying the amounts of protein remaining in the supported membranes after storage in buffer.

Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis.

Particular mucinous phenotypes have been associated with serrated epithelial polyps of the colon. These polyps also show a high frequency of DNA instability. The aim of this study was to examine the expression of mucins in colorectal cancers that arise through the suppressor and mutator pathways.

Anal cancer subtype reproducibility study.

For histological subtyping of anal squamous carcinomas the WHO advocates a six-way subdivision, but it has been suspected that the six types cannot be reliably discriminated in practice. We conducted a blinded study involving slides from 103 consecutive cases, each slide being examined by three experts (from Denmark, Australia and UK) on two occasions at least 8 months apart. Agreement on subtypes was low: 72% between rounds within pathologist, 61% between pathologists.

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.

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.

Towards a molecular classification of colorectal cancer.

The basic mechanisms driving genetic instability underlie a new molecular classification of colorectal cancer that is assuming diagnostic and prognostic importance. These mechanisms and the criteria for stratifying colorectal cancer as microsatellite stable (MSS), microsatellite instability-low (MSI-L) and microsatellite instability-high (MSI-H) are presented. This molecular classification is discussed in relation to morphogenesis, histopathology, behaviour and investigation of prognostic biomarkers in colorectal cancer.

Broadsheet number 52: Molecular genetics of colorectal cancer.

The molecular genetics of colorectal cancer is presented in an order that ascends from the basic to the applied: molecular mechanisms, morphogenesis, classification and diagnosis. Major consideration is given to the nature of genetic instability and the role of this mechanism in driving neoplastic progression. It is shown how the fundamental principle of genetic instability cuts across applied research, tissue diagnosis and clinical management with respect to both sporadic and inherited forms of colorectal cancer.

Infrequent loss of heterozygosity of APC/MCC and DCC genes in gastric cancer showing DNA microsatellite instability.

Aim: To investigate the role of DNA microsatellite instability (MSI) in gastric carcinogenesis by studying associations between MSI status, clinicopathological features, and loss of genetic loci.

Methods: Six microsatellite loci and loss of heterozygosity at APC, DCC, and MCC were analysed by polymerase chain reaction based methods in 53 cases of advanced gastric cancer.

Results: MSI was observed in 32.

Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways.

Background: 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H).

Aims: To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability.

Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability.

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two important determinants of angiogenesis in human cancers. Expression of VEGF and bFGF was examined by immunohistochemistry in 120 colorectal cancers. Neoplasms were classified according to the presence or absence of microsatellite instability determined at six microsatellite loci and labelled as a high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) or microsatellite stable (MSS).

Ultrastructural localization of epithelial mucin core proteins in colorectal tissues.

Mucins are high molecular weight glycoproteins with a variety of postulated biological functions, including physicochemical protection from toxins and mutagens, adhesion modulation, signal transduction, and regulation of cell growth. Mucins are widely and differentially expressed in the gastrointestinal tract. To date, studies of cellular expression have relied on light microscopy using in situ hybridization and immunohistochemistry.

Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum.

We studied the distribution of the four human apomucins MUC1, MUC2, MUC4, and MUC5AC in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum using immunohistochemical techniques, with the aim of comparing and contrasting their patterns of expression. A series of 12 hyperplastic polyps, 27 serrated adenomas, and 20 traditional adenomas was studied. No significant change in apomucin expression was observed in traditional adenomas compared with normal colorectal epithelium, except for MUC5AC, which was present in 12 of the adenomas (60%) and only 20% of the normal samples.

Serrated adenoma and colorectal cancer.

Hyperplastic polyps and serrated adenomas of the colorectum show mixed gastrointestinal differentiation, expressing both gastric (M1 or MUC5AC) and intestinal (MUC2) mucins. They also share the phenotype of mild DNA microsatellite instability (MSI-L). Recent findings of clonal genetic changes within hyperplastic polyps fit with a pathway of serrated neoplasia, perhaps culminating in the subset of colorectal cancer characterized by the mild mutator phenotype.