To review the present studies on early diagnosis of colorectal cancer.

The detective rate for early cancer is 1.7%-26.1% based on various statistical data, with much higher detective rate in endoscopy. Since early cancer means invasion involved in the mucosa or submucosa, the diagnosis can only be made when the invasive depth is identified. Pathological tissue materials from both surgical operation or endoscopic resection are suitable for early cancer evaluation.

Incidence of polyp malignancy is 1.4%-20.4%. The various constitutive proportion of polyps may explain the different rates. Malignant incidence is higher in adenomatous polyps, that for villous polyps can reach 21.3%-58.3%. Type II early stage of colorectal carcinoma is rarely reported in China. It is shown that majority of them were not malignant, most of type IIa being adenoma or hyperplasia, and IIb being inflammatory and IIc might be the isolated ulcers. The occurrence of malignancy of type II is far lower than that of polypoid lesion. In China, the qualitative diagnosis and classification of neoplasm generally adopted the WHO standard, including surgical excision or biopsies. There is impersonal evaluation between colorectal pre-malignancy and cancer. The former emphasizes the dysplasia of nuclei and gland, while the latter is marked with cancer invasion. Diagnosis of early stage colorectal cancer in endoscopy is made with too much caution which made the detective rate much lower. Mass screening for asymptomatic subjects and follow-up for high risk population are mainly used to find the early stage colorectal cancer in China. Fecal occult blood test is also widely made as primary screening test, galactose oxygenase test of rectal mucus (T antigen), fecal occult albumin test are also used. The detective rate of colorectal cancer is 24-36.5 per 105 mass population.

Although carcinoma associated antigen in blood or stool, microsatellite DNA instability for high risk familial history, molecular biology technology for stool oncogene or antioncogene, telomerase activity and exfoliative cytological examination for tumor marker, are utilized, none of them is used in mass screening by now.

The increasing number of genetic aberrations implicated in the development of human cancer has prompted a search to detect them at the earliest possible stage of their formation. Of the many such genetic changes identified thus far, relatively few meet the standard for markers in early diagnosis and prognosis, namely that the genetic modifications occur during the early onset phase of cancer development. Parallel to the increasing number of such genes is the growing availability of technologies using more powerful and cost-efficient methods that enable mass screening for genetic alterations. The purpose of this review is to summarize the currently available genes that can serve as markers for early detection of cancers and methods that allow their detection.

Colorectal cancer is one of the most common malignancies in the western world. About 60,000 Americans die of colorectal cancer each year. The annual incidence rate in Israel is 40 per 100,000 persons, namely a total of 2,000 new cases each year. An important step in the progression of colorectal cancer includes induction of activating mutations in the proto-oncogene K-ras. The mutations in K-ras appear early during tumorigenesis, at the intermediate adenoma stage, and thus can be used as a biomarker for early detection in about 40% of colonic tumors. A large yet unknown number of mutated cells are shed from the developing tumor during its progression. Indeed, K-ras mutations were detected in DNA isolated from stool obtained from symptomatic and asymptomatic patients with colorectal cancer, suggesting a novel approach for a noninvasive screening procedure. However, severe difficulties in obtaining reproducible yields of amplifiable DNA from stool, and usage of nonquantitative, time-consuming procedures, hampered further progress in the utilization of K-ras mutations for the early detection of colorectal cancer. Apparently a novel protocol is required that provides reproducible output of amplifiable DNA from small amounts of stool, detects if K-ras mutated DNA is present, and determines the quantity of K-ras mutated cells in the stool sample. In addition, this protocol should be simple, robotics compatible, and thus suitable for cost-effective, large-scale mutation screening. Molecular assays for detecting K-ras mutations and additional biomarkers in stool DNA promise to be highly sensitive, specific, and cost-effective. As such they should be very effective when used in chemoprevention studies and screening protocols for colorectal cancer.

Using arbitrarily primed polymerase chain reaction (AP-PCR) ribonucleic acid (RNA) fingerprinting, we discovered a messenger RNA (mRNA) that encoded the cytokine interleukin-8 (IL-8) that was up-regulated in the peripheral blood leukocytes (PBLs) of patients with metastatic prostate cancer (CaP) compared with similar cells from healthy individuals. We compared the total prostate-specific antigen (PSA) levels, the free/total (f/t) PSA ratios, and the immunoreactive IL-8 serum concentrations in patients with either biopsy-confirmed benign prostatic hyperplasia (BPH) or CaP.

The sera from 35 apparently healthy normal volunteers and 146 patients with biopsy-confirmed BPH and CaP obtained from two academic centers were retrospectively examined to determine the serum levels of IL-8, total PSA (tPSA), and the f/t PSA ratio. Logistic regression and trend analysis statistical methods were used to assess the results.

Normals (n = 35), BPH patients (n = 53), patients with clinical Stages A to C CaP (n = 81), and patients with metastatic CaP (n = 1 2) had mean levels of IL-8 of 6.8, 6.5, 15.6, and 27.8 pg/mL, respectively. The IL-8 serum concentrations correlated with increasing CaP stage and also differentiated BPH from clinical Stages A, B, C, or D CaP better than tPSA and performed similarly to the f/t PSA ratio. The combination of the IL-8 levels and f/t PSA ratios using multivariate logistic regression analysis distinguished BPH from Stages A, B, C, or D CaP or only Stages A and B with a receiver operating characteristic area under the curve of 89.8% and 87.5%, respectively (P <0.0001).

The IL-8 serum concentration in our clinically well-defined patient sample was independent of the f/t PSA ratio as a predictor of CaP. When test samples are controlled for extraneous clinical origin of inflammation or infection, the combination of the IL-8 and f/t PSA assay results may offer an improved approach for distinguishing BPH from CaP.

We have briefly surveyed some the developments in the field of molecular diagnostics that provide a basis for cautious optimism about progress in population-based early lung cancer screening. The sound lung cancer management strategies that were formulated several decades ago failed in clinical trials because the necessary tools to implement the strategies were not yet available. Technology is beginning to emerge that makes population-based screening achievable. This same technology may be used to define a comprehensive marker panel including the most informative markers from the long list of candidate markers. Validation studies will define more clearly the strengths and limitations of new molecular diagnostics and provide leads for further research attention. The clinical community can expedite this process if these validation efforts are aggressively pursued. Parallel developments are clearly needed in refining the range of therapeutic intervention for early cancer management. The success of both diagnostic and intervention tools is interwoven in the ultimate goal of reducing lung cancer mortality. This article is an invitation to think expansively about new approaches to cancer care that integrate the fruits of our hard-learned lessons.

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC), accounting for approximately 10% of the total CRC burden. HNPCC lacks premonitory physical stigmata, thereby making the family history crucial for diagnosis. Advances in molecular genetics during the past 2 years have led to the cloning of four HNPCC genes (MHS2, MLH1, PMS1 and PMS2). It is now possible to provide presymptomatic DNA testing followed by genetic counselling for gene carriers. Some studies have shown that adenomas in HNPCC are larger, more villous, and have more high grade dysplasia than sporadic cases, suggesting an accelerated adenoma-carcinoma sequence. Given the early age of onset and proximal predominance of CRC, we initiate colonoscopy at age 20-25 years and we recommend that it be performed every 1-2 years. The wealth of clinical and molecular genetic knowledge currently available to physicians about HNPCC can be used effectively for cancer control.

Clonality is a fundamental characteristic of all human cancers. One cancer cell gives rise to daughter cells, all of which exhibit the same change that initially provided a growth advantage to the parent cell. Accumulation of further genetic changes in subsequent daughter cells, each providing an additional growth advantage, has been well documented in human cancer. Correlation of these clonal genetic changes with histopathological progression has led to development of a molecular progression model for colorectal cancer. The identification of genetic markers able to identify the clonal outgrowth of neoplastic cells has proven useful in the detection of a variety of primary neoplasms.

The best way to reduce the incidence of colorectal cancer mortality would be to prevent this cancer. However, none of the biomarkers proposed can accurately identify persons at increased risk of colorectal cancer or those at low risk. As a possible genetic biomarker, K-ras mutations, which are frequently found in colorectal cancers, were analyzed in apparently normal colorectal mucosa.

Nonneoplastic mucosa and tumor tissues were collected at surgery from 70 patients with colorectal cancer: one sample each from 50 patients (group A) and multiple samples from the other 20 patients (group B). Mutant K-ras codon 12 was analyzed by the enriched polymerase chain reaction (EPCR), by which one mutant can be detected among 10(3) to 10(4) normal alleles.

Only with the aid of EPCR was mutant K-ras detected in nonneoplastic mucosa of nine patients (18%) in Group A and five patients (25%) in Group B. This increased incidence could be attributed to the multiple tissue sampling. The presence of mutant K-ras in nonneoplastic mucosae was not consistently correlated with that in the tumors. These findings suggest that the mutant K-ras identified in nonneoplastic mucosa actually represents de novo mutations, which may be initiated by different etiologic factors and at different times.

Mutant K-ras detected in apparently normal mucosa should be a useful biomarker for identifying persons at higher risk of colorectal cancer. Our study also emphasizes the need for improving the method for sample collection to achieve true representation of the colorectal mucosa.