ABSTRACT
Screening programs for colorectal cancer (CRC) are standard in most developed countries because they reduce mortality and are cost-effective. Within them, colonoscopy allows to directly visualize the colon and remove neoplastic lesions. However, it is an expensive exam with low adherence in asymptomatic individuals. The fecal occult blood test (FOBT) is a low-cost and risk-free method for the user, which results in a high rate of adherence, explaining its use in most screening programs. This article analyzes the effectiveness of different fecal occult blood tests in screening programs. The main conclusions are that the sensitivity of the guaiac-based chemical test for the detection of colorectal cancer is lower than that observed with qualitative and quantitative immunological tests. Automated quantitative methods allow objective readings independent of the operator and the reaction reading time, necessary for the analysis of large numbers of samples. The participation rate with immunological FOBTs is higher than with chemical ones, which is why they are preferred by the different countries that have screening programs. The use of quantitative tests allows stratification of symptomatic and asymptomatic patients at higher risk, in the screening programs.
Subject(s)
Humans , Colorectal Neoplasms/diagnosis , Occult Blood , Mass Screening , Colonoscopy , Early Detection of Cancer , GuaiacABSTRACT
Background: Colorectal cancer (CRC) is an heterogeneous disease. Three carcinogenic pathways determine its molecular profile: microsatellite instability (MSI), chromosomal instability (CIN) and CpG island methylator phenotype (CIMP). Based on the new molecular classification, four consensus CRC molecular subtypes (CMS) are established, which are related to clinical, pathological and biological characteristics of the tumor. Aim: To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways. Material and Methods: Prospective analytical study of 53 patients with a mean age of 70 years (55% males) with CRC, operated at a private clinic, without neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, MSI and CIMP were analyzed. Combining these variables, tumors were classified as CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal. Results: CMS1 tumors (19%) were located in the right colon, were in early stages, had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors (29%) were also left-sided, with absence of vascular and lymphatic invasion, and 29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed advanced stages and presence of metastases. Conclusions: This new molecular classification contributes to understanding the heterogeneity of tumors. It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma, opening the door to personalized medicine.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , DNA, Neoplasm/genetics , Colorectal Neoplasms/genetics , Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , DNA Methylation/genetics , Microsatellite Instability , Phenotype , Colorectal Neoplasms/pathology , Adenocarcinoma/pathology , Chile , Prospective Studies , Consensus , MutationABSTRACT
Background: In Chile, colorectal cancer (CRC) is often diagnosed in late stages. Thus, surgical treatment must be complemented with chemotherapy. KRAS mutations and microsatellite instability have been detected in these tumors. However, the response to treatment in patients without KRAS mutations varies and requires a better understanding. Aim: To determine the frequency and distribution of somatic point mutations in KRAS, BRAF and PIK3CA genes and microsatellite instability status (MSI) in patients with colon cancer (CC). Material and Methods: A prospective observational study of patients undergoing surgery for colon cancer. Tumor-derived DNA was analyzed by polymerase chain reaction (PCR) for the most frequent mutations of KRAS, BRAF and PIK3CA. PCR was also used to analyze MSI. Results: Fifty-eight patients with sporadic CC were analyzed, 16 showed KRAS mutations (G12R, G12D, G12V, G13D) and out of the 42 patients that did not show any mutation, 10 had mutations in BRAF (V600E) and PIK3CA (E542K, E545D, E545K, Q546E, H1047R). BRAF mutations alone or in combination with PIK3CA mutations were observed in 27% of high MSI tumors and in 2% of tumors without instability (p < 0.049). A higher percentage of high MSI tumors were located in the right colon (p < 0.001), and showed BRAF mutation (p < 0.020). Conclusions: The highest percentage of high MSI and BRAF mutations was observed in the right colon. Therefore, this study suggests the presence of different molecular features between right and left colon tumors that should be considered when defining the therapeutic management.
Subject(s)
Animals , Mice , Interferon Type I/immunology , Interferon-gamma/immunology , /immunology , /immunology , Interleukins/immunology , Macrophages/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Interferon Type I/genetics , Interferon-gamma/genetics , /genetics , /genetics , Interleukin-1beta/immunology , Interleukins/genetics , Macrophage Activation/immunology , Macrophages/microbiology , Macrophages/pathology , Mice, Knockout , Tuberculosis/genetics , Tuberculosis/pathology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Background: The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti-epidermal growth factor receptor monoclonal antibody therapy. Aim: To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer (CRC). Material and Methods: A cohort of 262 Chilean patients with CRC aged 26 to 90 years (53% males), was studied. KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data. Results: Ninety-eight patients (37%) were positive for KRAS mutations. G12D was the most common mutation with a frequency of 36.7%, followed by G12V (25.5%), G13D (17.3%), G12A (7.1%), G12C (6.1%), G12S (5.1%) and G12R (2%). The frequency of the mutation in left, right colon and rectal tumors was 37.8, 32.6 and 44.9%, respectively. Among tumors with mutations, 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated. No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed. Conclusions: The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North-American populations, lower than in a Spanish study and higher than in a Peruvian study.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Colorectal Neoplasms/genetics , Mutation , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Age Factors , Chile/ethnology , Colorectal Neoplasms/ethnology , Colorectal Neoplasms/pathology , DNA Mutational Analysis , DNA, Neoplasm/genetics , Epidermal Growth Factor/genetics , Neoplasm Invasiveness/genetics , Prospective Studies , Real-Time Polymerase Chain Reaction , Sex FactorsABSTRACT
Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.
Subject(s)
Adult , Female , Humans , Adenomatous Polyposis Coli/genetics , DNA Glycosylases/genetics , Germ-Line Mutation/genetics , Genetic Predisposition to Disease/etiology , Homozygote , Pedigree , Polymerase Chain ReactionABSTRACT
Background: Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Im-munohistochemistry (IHC) in the tumor has been proposed. Aim: To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. Material and Methods: From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. Results: A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. Conclusions: MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes.
Subject(s)
Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Germ-Line Mutation , Microsatellite Instability , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Repair/genetics , Genetic Testing , ImmunohistochemistryABSTRACT
Background: Mortality from colorectal cancer (CCR) in Chile has nearly doubled over the past 15 years. International studies have shown that CCR screening programs based on fecal occult blood test (FOBT) reduce CCR mortality. Aim: To analyze the results from a CCR screening model in people over 50 years. Material and Methods: Between 2007 and 2009, a prospective multicenter study was performed in seven major Chilean cities. FOBT using an immunological method, was measured in asymptomatic subjects aged 50 years or more, without risk factors. In patients with a positive FOBT, with symptoms or with family risk factors, a colonoscopy was indicated. Results: A total of 6348 subjects were assessed, FOBT was performed in 4938 of them, with a compliance of 77%. The result was positive in 9.6%. A total of 2359 colonoscopies were ordered, with an overall compliance of 50.1%. Of the 1184 colonoscopies performed, adenomas and high risk adenomas were found in 304 (26%) and 75 (6%) patients, respectively. Thirteen patients were diagnosed with stage I and IICCR. Three of these lesions were excised endoscopically and 10 surgically. The detection rate of polyps, high risk adenomas and cancer was 75, 12 and 2 per 1000 screened individuals, respectively. Conclusions: This program allowed the early detection of an important number of high risk colon lesions, and all patients with CCR were diagnosed at early stages.
Subject(s)
Humans , Middle Aged , Adenomatous Polyps/diagnosis , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/methods , Mass Screening/methods , Occult Blood , Adenomatous Polyps/mortality , Age Factors , Chile/epidemiology , Colonoscopy , Colorectal Neoplasms/mortality , Patient Compliance , Program Evaluation , Prospective Studies , Risk Factors , Urban PopulationABSTRACT
Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome is an autosomic dominant syndrome involving 596-1096 of colorectal cancer patients. Mutations in MLH1 and MSH2 genes account for most cases. These two genes particípate in the DNA mismatch repair pathway. Therefore mutation carriers show microsatellite instability (MSI) in tumors. This syndrome is characterized by the early development of colorectal cancer (before 50 years) and an increased incidence of cancer in other organs. We report four siblings from a family diagnosed with HNPCC. All of them were subjected to colonic surgery for colorectal cancer Moreover, one patient developed an ampulloma after her colon surgery. The molecular-genetic analysis revealed three brothers with microsatellite instability in the tumor tissue, the absence of the MLH1 protein, and the presence of a germ Une mutation localized in introm 15 ofthe MLH1 gene.