Whilst individual planning of treatment and follow-up in every colorectal cancer case is an increasing demand, prognostic markers are needed for predicting cancer progression in the primary phase. We ...studied the effect of replication error (RER)-positivity on colorectal cancer progression by analysing 255 colorectal cancer specimens by polymerase chain reaction (PCR) and fragment analysis and correlating the results with the clinical and histological features of the tumour and with patient outcome. RER-positivity was detected in 12% (28/235) of cases. It was associated with proximal location of the tumour (P<0.001), poor differentiation (P=0.001) and large tumour size (P=0.009). The 5-year cumulative survival rate of the patients with RER-positive cancer of the proximal colon was markedly better (100%) than that of those with RER-negative proximal cancer (74%), whilst in cases of cancer of the distal colon or rectum, RER-positivity (21%) indicated poorer survival than RER-negativity (57%). Thus, it is suggested that RER-positivity has an opposite impact on cancer progression in cases of proximal and distal cancers. RER-positivity appears to indicate improved prognosis only in cases of proximally located cancer, in which it could accordingly be useful as a prognostic marker.
We report here the use of multiplex fluorescent polymerase chain reaction (PCR) for quantitative allele loss detection using microsatellites with 2-5 base pair repeat motifs. Allele loss of APC, DCC, ...p53 and RB1 in colorectal tumours has been reported previously using a variety of methods. However, not all workers used intragenic markers. We have used microsatellite polymorphisms which map within, or are closely linked to, these tumour-suppressor gene loci in order to determine whether these loci are indeed the targets for alteration in colorectal cancer. In addition, we have assayed two other tumour-suppressor genes, WT1 and NF1, to see whether they play a role in colorectal carcinogenesis. The putative metastasis-suppressor gene, NM23, was also investigated since there have been conflicting reports about its involvement in colorectal carcinogenesis. Allele loss was detected at the DCC (29%), p53 (66%), RB1 (50%) and NF1 (14%) loci and in the APC/MCC region (50%), but not at the WT1 or NM23 loci. These rapid, and mostly gene-specific, fluorescent multiplex PCR assays for allele loss detection could be modified to devise a single molecular diagnostic test for the important lesions in colorectal cancer.
HEBBAR M., FOURNIER P. & ROMANO O. (2010) European Journal of Cancer Care19, 145–166 KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications so ...clear?
The CRYSTAL study demonstrated an advantage in terms of objective response and progression‐free survival for the FOLFIRI–cetuximab combination compared with first‐line FOLFIRI for patients with metastatic colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540 patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend restriction of the use of cetuximab in Europe to patients with a tumour bearing wild‐type KRAS. How should this apparent simplification be integrated into clinical practice? The FOLFIRI–cetuximab combination is certainly a useful supplementary first‐line option although its place in relation to other high‐dose regimens (high‐dose FOLFIRI, FOLFOXIRI or FOLFOX‐7), conventional chemotherapy plus bevacizumab, or even a fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no study has prospectively assessed the value of the chemotherapy–anti‐epidermal growth factor receptor combination as a function of KRAS status. Should the absence of objective response constantly observed in retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these patients while stable disease (and potentially a slight gain in survival) may be obtained?
We investigated the frequency and clinical significance of loss of heterozygosity (LOH) at the APC, MCC, and DCC tumor suppressor gene loci in 108 cases of resected non-small cell lung cancer ...(NSCLC). LOH at the APC/MCC gene cluster at chromosome 5q21 occurred frequently; it affected 29% of informative NSCLC cases and correlated with a significantly worse survival (P < 0.01). Furthermore, in the subtype most frequently affected (SCC), LOH at 5q not only correlated with a worse survival but also tumor involvement of the mediastinal and/or hilar nodes. In contrast, LOH at the DCC locus at chromosome 18q was far less frequent, occurring in 14% of NSCLC cases, and it was not associated with advanced stage or prognosis. These data suggest that LOH at 5q has a role in determining tumor progression and survival in NSCLC, and may prove to be a clinically useful prognostic indicator.
The genes that are mutated in two of the rare syndromes of hereditary colon cancer were recently identified, and genetic diagnosis is already possible in some cases. Acquired mutations of these same ...genes also appear to be important in sporadic colon cancers. Familial clustering of sporadic cases is common and may likewise arise from inherited susceptibility. Screening strategies for both the rare syndromes and the common cases of colon cancer with familial risk have been suggested. Certain clinical features allow stratification of colon cancer risk among common cases. It is anticipated that continued genetic investigation will result in more precise screening and improved diagnostic and therapeutic options for colon cancer.
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 32.1% of gastric carcinomas (17/53) and 20% of foci of intestinal metaplasia (3/15). Seven gastric carcinomas (13.7%) were MSI-high (MSI-H) (three loci or more) and 10 (18.9%) were MSI-low (MSI-L) (one or two loci). The frequency of MSI-H was higher in intestinal (25.0%) than in diffuse carcinomas (3.7%) (p < 0.05). None of the MSI-H tumours showed loss of heterozygosity at APC, MCC, or DCC loci. CONCLUSIONS: MSI may have an important and early role in a subset of gastric cancers, particularly the intestinal type. The MSI-H subset of gastric cancer has features in common with its colorectal counterpart, whereas MSI-L and microsatellite stable cancers appear to develop through the loss of heterozygosity pathway.
It is unclear whether synchronous multiple tumors arise from multicentric or monoclonal origins. To verify the multicentric origin of synchronous colorectal carcinomas at a genetic level, ...immunohistochemical and molecular techniques were used to determine the p53 alterations in individual lesions of synchronous colorectal carcinomas. This study was based on a total of 32 colorectal tumors from 16 patients. Twenty-one of the 32 (66%) advanced tumors examined had positive staining for p53. Single-strand conformation polymorphism and polymerase chain reaction direct sequencing were carried out for exons 5 to 8 of p53. All cases had p53 mutations in one or more tumors of synchronous lesions. In nine patients in this series, individual lesions were found to carry a different mutated codon of the p53 gene. In the other seven patients, a p53 mutation was found in one tumor but not in another. These results indicate discordance of the mutation pattern of p53 in individual lesions of multiple colorectal carcinomas and support the idea that most synchronous colorectal carcinomas are genetically distinguishable and are multicentric in origin. We also confirmed the high frequency of p53 mutations in left-sided (71%) and rectal (91%) carcinomas, rather than right-sided (43%; P =.04) carcinomas, suggesting that the molecular mechanism of synchronous colorectal carcinomas might differ between right- and left-sided tumors in the same patient.
Background: Loss of heterozygosity (LOH) at tumor suppressor genes, such as adenomatous polyposis coli (APC) and mutated in colon cancer (MCC) genes, is one of the early events in carcinogenesis of ...oral tissue in Caucasian and Chinese patients. We wanted to check whether it is also true in Indian oral pre‐cancer and cancer patients.
Methods: Loss of heterozygosity at APC and MCC genes was investigated in 57 and 40 unrelated primary oral leukoplakia (a pre‐cancerous lesion) and squamous cell carcinomas (SCC), respectively, by polymerase chain reaction.
Results: In these samples, most of the leukoplakia patients had tobacco smoking habit whereas majority of cancer patients had tobacco chewing habit. LOH at APC gene was observed in 4 of 16 (25%) and 1 of 29 (3%) informative tumor and leukoplakia DNAs from tobacco chewers, respectively. LOH at MCC gene was not detected either in tumor or in leukoplakia DNAs.
Conclusion: This infrequent LOH at APC gene of pre‐cancer and cancer tissues suggests that it may not be an early event in oral carcinogenesis in these patients.
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