ABSTRACT
KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.
Subject(s)
Carcinoma/genetics , Carcinoma/pathology , Colonic Polyps/genetics , Colonic Polyps/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Mutation , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Carcinoma/mortality , Cell Differentiation , Chi-Square Distribution , Colonic Polyps/mortality , Colorectal Neoplasms/chemistry , Colorectal Neoplasms/mortality , DNA Methylation , DNA Modification Methylases/analysis , DNA Modification Methylases/genetics , DNA Mutational Analysis , DNA Repair Enzymes/analysis , DNA Repair Enzymes/genetics , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Microsatellite Instability , Middle Aged , Phenotype , Prognosis , Proportional Hazards Models , Prospective Studies , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Risk Factors , Time Factors , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/genetics , VictoriaABSTRACT
Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma.
Subject(s)
Adenoma/pathology , Colon/pathology , Colonic Polyps/pathology , Colorectal Neoplasms/pathology , Adaptor Proteins, Signal Transducing/metabolism , Adenoma/genetics , Adenoma/metabolism , Adenosine Triphosphatases/metabolism , Adolescent , Adult , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Colectomy , Colonic Polyps/genetics , Colonic Polyps/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , DNA Mutational Analysis , DNA Repair Enzymes/metabolism , DNA, Neoplasm/genetics , DNA-Binding Proteins/metabolism , Female , Humans , Hyperplasia/genetics , Hyperplasia/metabolism , Hyperplasia/pathology , Male , Middle Aged , Mismatch Repair Endonuclease PMS2 , MutL Protein Homolog 1 , Mutation , Nuclear Proteins/metabolism , Phenotype , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Syndrome , Young Adult , ras Proteins/geneticsABSTRACT
Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.
Subject(s)
Adenomatous Polyps/pathology , Colonic Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair , DNA-Binding Proteins/metabolism , Immunohistochemistry/methods , Adenomatous Polyps/genetics , Adenomatous Polyps/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , DNA Mutational Analysis , DNA, Neoplasm/analysis , Family Health , Female , Genetic Predisposition to Disease , Germ-Line Mutation , Heterozygote , Humans , Male , Middle Aged , Young AdultABSTRACT
Oncogenic PIK3CA mutations contribute to colorectal tumorigenesis by activating AKT signaling to decrease apoptosis and increase tumor invasion. A synergistic association of PIK3CA mutation with KRAS mutation has been suggested to increase AKT signaling and resistance to antiepidermal growth factor receptor inhibitor therapy for advanced colorectal cancer, although studies have been conflicting. We sought to clarify this by examining PIK3CA mutation frequency in relation to other key molecular features of defined pathways of tumorigenesis. PIK3CA mutation was assessed by high resolution melt analysis in 829 colorectal cancer samples and 426 colorectal polyps. Mutations were independently correlated with clinicopathological features including patient age, sex and tumor location as well as molecular features including microsatellite instability, KRAS and BRAF mutation, MGMT methylation and the CpG Island Methylator Phenotype (CIMP). Mutation of the helical (Exon 9) and catalytic (Exon 20) domain mutation hotspots were also examined independently. Overall, PIK3CA mutation was positively correlated with KRAS mutation (p < 0.001), MGMT methylation (p = 0.007) and CIMP (p < 0.001). Novel, exon-specific associations linked Exon 9 mutations to a subgroup of cancers characterized by KRAS mutation, MGMT methylation and CIMP-Low, whilst Exon 20 mutations were more closely linked to features of serrated pathway tumors including BRAF mutation, microsatellite instability and CIMP-High or Low. PIK3CA mutations were uncommonly, but exclusively, seen in tubulovillous adenomas (4/124, 3.2%) and 1/4 (25.0%) tubulovillous adenomas with a focus of cancer. These data provide insight into the molecular events driving traditional versus serrated pathway tumorigenesis.
Subject(s)
Colonic Polyps/genetics , Colorectal Neoplasms/genetics , Oncogenes , Phosphatidylinositol 3-Kinases/genetics , Aged , Base Sequence , Class I Phosphatidylinositol 3-Kinases , Cohort Studies , DNA Primers , Female , Humans , Male , Middle AgedABSTRACT
Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
Subject(s)
Chromosomes, Human, Pair 2 , Colorectal Neoplasms/genetics , Genetic Linkage , Genetic Predisposition to Disease , Adult , Aged , Chromosome Mapping , Female , Genome-Wide Association Study , Haplotypes , Humans , Lod Score , Male , Middle Aged , SyndromeABSTRACT
OBJECTIVE: Hyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery. METHODS: One hundred and twenty-six patients with multiple (> or = 5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening. RESULTS: The average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P = 0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P = 0.03) and were more likely to have their CRC in the distal colon (P = 0.02). CRC was significantly associated with the presence of adenomas (P = 0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P = 0.034) and male gender (P = 0.014), independent of ascertainment status and recruitment site. CONCLUSION: Multiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps.
Subject(s)
Colonic Polyps/genetics , Colonic Polyps/pathology , Female , Humans , Male , Middle Aged , Phenotype , Regression Analysis , Risk FactorsABSTRACT
Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Exons , Founder Effect , Base Sequence , Blotting, Southern , DNA Primers , DNA, Complementary , Haplotypes , Humans , Immunohistochemistry , QuebecABSTRACT
Predicting patient outcome for colorectal carcinoma (CRC) with lymph node but not distant metastases remains challenging. Various prognostic markers have been identified including microsatellite instability (MSI) and possibly expression of the MHC Class II protein, HLA-DR. About 15% of sporadic CRC exhibits MSI associated with methylation of the DNA mismatch repair gene hMLH1 promoter. In addition, a significant proportion of unselected CRC demonstrates expression of HLA-DR. We sought to examine the relationship between HLA-DR expression, MSI status and prognosis in sporadic Australian Clinicopathological (ACP) Stage C CRC. Two hundred seventy consecutive patients with sporadic ACP Stage C CRC were treated at Concord Repatriation General Hospital between 1986 and 1992. None of these patients received adjuvant chemotherapy and all were followed for a minimum of 5 years or until death. DNA was extracted from paraffin sections and MSI status determined by PCR. HLA-DR expression was determined immunohistochemically using an antibody against the HLA-DR alpha chain. MSI status could be assigned in 235 cases: 176 CRCs (74.9%) were microsatellite stable, whereas 23 (9.8%) had high levels of MSI (MSI-H) and 36 (15.3%) had low levels of MSI (MSI-L). HLA-DR expression by CRC cells was seen in 148 (60.1%) cases and correlated with the presence of tumor-infiltrating lymphocytes (p = 0.0005) and peritumoral lymphocytes (p = 0.003), but not other clinicopathological features or MSI status. HLA-DR-positive CRCs were strongly associated with better patient outcome (p < 0.0001).
Subject(s)
Colorectal Neoplasms/metabolism , HLA-DR Antigens/metabolism , Microsatellite Repeats/genetics , Adult , Aged , Aged, 80 and over , Australia , Cohort Studies , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Female , HLA-DR Antigens/genetics , Humans , Immunoenzyme Techniques , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival RateABSTRACT
Family history is a strong predictor of colorectal cancer risk; however, a diagnosis of colorectal cancer among first-degree relatives has not been systematically investigated as a function of the colorectal cancer molecular subtypes related to tumor microsatellite instability (MSI) status. We investigated whether the observable familial colorectal cancer risks differed according to tumor MSI subtypes, stratified as MSI-High (>30% instability), MSI-Low (<30% instability), and MSS (no instability). Data from 3,143 population-based colorectal cancer cases from five institutions were assessed for family history according to the Amsterdam criteria and the Bethesda guidelines, age at diagnosis, sex, tumor location, and MSI status. The distribution of patient characteristics by MSI status was compared using polytomous logistic regression. Overall, 2.8% colorectal cancer cases met the Amsterdam criteria and 37% met the Bethesda guidelines. There were 14% MSI-High, 13% MSI-Low, and 73% MSS colorectal cancers. MSI-High (P<0.0001) and MSI-Low tumors (P=0.01) were more proximally located than MSS tumors. MSI-High tumors were more common among females (P<0.001). The highest proportion of MSI-High tumors occurred in cases<40 years of age whereas the age-dependent distribution of MSI-Low tumors was unchanged. MSI-High tumors showed a statistically significant association with increasing numbers of first-degree relatives with colorectal cancer (P=0.002); this association disappeared, however, when MSI-High cases meeting Amsterdam criteria were removed from the analysis. MSI-Low tumors did not show a similar association with family history of colorectal cancer. Familial risk associated with MSI-High tumors is primarily driven by the Amsterdam-criteria patients. MSI-Low tumors may represent a distinct subtype of colorectal cancer with respect to certain epidemiologic variables studied here.
Subject(s)
Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Microsatellite Instability , Adolescent , Adult , Aged , Female , Humans , Logistic Models , Male , Middle Aged , Phenotype , Risk AssessmentABSTRACT
The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered "sporadic" due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.
Subject(s)
Colonic Polyps/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adenoma/genetics , Adenoma/pathology , Adult , Aged , Colonic Polyps/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Male , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/genetics , MutS Homolog 2 Protein/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Pedigree , Polymerase Chain Reaction , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
The healthy colorectal mucosa contains many resident intraepithelial lymphocytes (IELs) consisting of partially activated yet hyporesponsive CD8(+) T cells. A predominant feature of colorectal cancers (CRCs) characterized by high levels of microsatellite instability (MSI-H) is heavy infiltration by an intraepithelial population of tumor infiltrating lymphocytes (iTILs). While it has been assumed that these iTILs originate from tumor infiltration by peripheral CD8(+) effector T cells, their origin remains unknown. In light of the phenotypic and functional differences exhibited by IELs and peripheral T cells, elucidation of the precursor population of iTILs in MSI-H CRCs could clarify the role played by these lymphocytes in tumor progression. The aim of the present study was to investigate whether MSI-H CRCs interact differently with IEL- versus peripherally-derived CD8(+) T cells. Using a Transwell assay system to mimic basolateral infiltration of tumor cells by lymphocytes, T cell migration, retention, proliferation and phenotypic alterations were investigated. Results indicate that MSI-H CRCs preferentially retain and expand IEL-derived cells to a greater degree than their microsatellite stable (MSS) counterparts. While MSI-H CRCs also retained more peripherally derived T cells, this number was considerably less than that from the IEL population. While interaction of IELs with either CRC type led to baseline lymphocyte activation, MSS CRCs induced upregulation of additional activation markers on retained IELs compared to MSI-H CRCs. These results suggest that the abundant iTILs present in MSI-H CRCs result from expansion of the preexisting mucosal IEL population and imply a limited prognostic role for iTILs in MSI-H CRC.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Intestinal Mucosa/metabolism , Microsatellite Instability , Cell Line, Tumor , Flow Cytometry , Humans , Intestinal Mucosa/immunologyABSTRACT
BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. RESULTS: Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. CONCLUSIONS: The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)
Subject(s)
Adenoma/prevention & control , Aspirin/therapeutic use , Carcinoma/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms/prevention & control , Starch/therapeutic use , Adenoma/epidemiology , Adult , Aged , Aspirin/administration & dosage , Aspirin/adverse effects , Carcinoma/epidemiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Drug Therapy, Combination , Female , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Risk , Starch/adverse effects , Treatment FailureSubject(s)
Adenocarcinoma/pathology , Colorectal Neoplasms/pathology , Intestinal Mucosa/pathology , Precancerous Conditions/pathology , Adenocarcinoma/physiopathology , Adenoma/pathology , Adenoma/physiopathology , Adenomatous Polyps/pathology , Adenomatous Polyps/physiopathology , Biopsy, Needle , Colonoscopy/methods , Colorectal Neoplasms/physiopathology , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Male , PrognosisABSTRACT
The colorectal polyposes are uncommon and frequently present diagnostic difficulties. Although the final diagnostic arbiter is the demonstration of a germline mutation, this may not always be demonstrable, and some forms of colorectal polyposis have no known genetic basis. Therefore, an accurate description of the phenotype by the pathologist is central to the establishment of a working diagnosis. This can direct the search for the underlying genetic cause (if any) and is also essential for establishing the magnitude of risk of colorectal malignancy for the patient and the patient's relatives. The pathologist may be provided with only a small and selected sample of endoscopically resected polyps or with prodigious numbers of polyps (too many to sample) when receiving a surgical specimen. Each type of polyposis presents its own particular diagnostic problems that may relate to polyp numbers, gross recognition of small or flat polyps, incomplete development of the full phenotype at the stage of investigation, and the histological classification of unusual or mixed polyps. The aim of this review is to highlight the principles and pitfalls in achieving a comprehensive description of the various types of colorectal polyposis, including classical FAP, attenuated FAP, MUTYH- (formerly MYH-) associated polyposis (MAP), other presentations of multiple adenomas, Peutz-Jeghers syndrome (P-JS), juvenile polyposis syndrome (JPS), Cowden syndrome (CS), hereditary mixed polyposis syndrome (HMPS), and hyperplastic polyposis syndrome (HPS).
Subject(s)
Colorectal Neoplasms/diagnosis , Intestinal Polyposis/diagnosis , Colorectal Neoplasms/genetics , Endoscopy, Gastrointestinal , Genes, Neoplasm , Genetic Predisposition to Disease , Humans , Intestinal Polyposis/classification , Intestinal Polyposis/genetics , PhenotypeABSTRACT
PURPOSE: A woman with early-onset endometrial cancer (EC) may represent the "sentinel" cancer event in a Lynch syndrome kindred. The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder. EXPERIMENTAL DESIGN: Patients with EC, ages < or =50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available. RESULTS: Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II, diagnosis of a Lynch syndrome spectrum cancer in at least one first-degree relative, and family history of any cancer (P < 0.05). CONCLUSION: Presumptive Lynch syndrome was identified in 18% of early-onset EC. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.
Subject(s)
Carcinoma, Endometrioid/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Endometrial Neoplasms/diagnosis , Neoplasms, Multiple Primary/diagnosis , Adaptor Proteins, Signal Transducing/genetics , Adult , Age Factors , Age of Onset , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/metabolism , Carcinoma, Endometrioid/pathology , DNA Methylation , DNA Mismatch Repair , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/metabolism , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/metabolism , Neoplasms, Multiple Primary/pathology , Nuclear Proteins/geneticsABSTRACT
Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways.
Subject(s)
Adenocarcinoma/genetics , Bone Morphogenetic Proteins/physiology , Cell Transformation, Neoplastic/genetics , Colorectal Neoplasms/genetics , DNA Methylation , Genes, Tumor Suppressor , Adaptor Proteins, Signal Transducing/genetics , Adenocarcinoma/metabolism , Adenoma/genetics , Adenoma/metabolism , Bone Morphogenetic Protein 3 , Cell Line, Tumor , Cohort Studies , Colonic Polyps/genetics , Colonic Polyps/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , CpG Islands , Disease Progression , Humans , Intestinal Mucosa/metabolism , Loss of Heterozygosity , Microsatellite Instability , MutL Protein Homolog 1 , Nuclear Proteins/genetics , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , Promoter Regions, Genetic/genetics , Subtraction Technique , Tumor Stem Cell AssayABSTRACT
There is now strong evidence for an alternative pathway of colorectal carcinogenesis implicating hyperplastic polyps and serrated adenomas. This article briefly reviews the evidence for this serrated pathway, provides diagnostic criteria for clinically significant hyperplastic polyps and allied serrated polyps, and suggests how this information may be translated into safe, effective guidelines for colonoscopy-based colon cancer prevention. Consideration also is given to the definition and management of hyperplastic polyposis syndrome. The currently proposed management plan for serrated polyps is tentative because of incomplete knowledge of the nature and behavior of these polyps. This article highlights key areas warranting further research.
Subject(s)
Adenoma , Colonic Neoplasms , Colonic Polyps , Colonoscopy/methods , Molecular Biology/methods , Oncogenes/genetics , Adenoma/classification , Adenoma/diagnosis , Adenoma/genetics , Colonic Neoplasms/classification , Colonic Neoplasms/diagnosis , Colonic Neoplasms/genetics , Colonic Polyps/classification , Colonic Polyps/diagnosis , Colonic Polyps/genetics , DNA, Neoplasm/analysis , Diagnosis, Differential , Genetic Predisposition to Disease , Humans , Prognosis , Severity of Illness IndexABSTRACT
PURPOSE: To identify independent clinicopathologic factors and protein markers leading to the identification of colorectal cancer (CRC) patients with mismatch repair proficiency at risk of developing metastasis and, consequently, more likely to benefit from combined modality therapy. EXPERIMENTAL DESIGN: Immunohistochemistry for 22 tumor markers was done using a tissue microarray. A subset of 387 CRC patients with complete clinicopathologic data and TNM stage was analyzed. Univariate and multivariate analyses were done to identify independent predictive markers of metastasis. The results were validated on 810 CRC patients. RESULTS: In univariate analysis, T stage (P < 0.001), N stage (P < 0.001), tumor grade (P = 0.005), vascular invasion (P < 0.001), tumor budding (P < 0.001), positive expression of beta-catenin (P = 0.015), overexpression of RHAMM (P = 0.008), negative expression of Raf-1 kinase inhibitor protein (RKIP; P = 0.001), and absence of intraepithelial lymphocytes (P = 0.017) were significantly associated with the presence of distant metastasis. In multivariate analysis, higher N stage (P < 0.001), presence of vascular invasion (P = 0.009), and RKIP loss (P = 0.003) independently predicted distant metastatic disease. A subgroup of node-negative patients was identified as high risk for distant metastasis and showed a similar probability of metastatic risk and nearly identical survival times as node-positive patients with absence of vascular invasion and positive RKIP expression (metastatic risk, 24% and 22%; median survival time, 45.0 and 47.0 months, respectively). CONCLUSION: The combined analysis of N stage, vascular invasion, and RKIP expression is highly predictive of distant metastasis in patients with mismatch repair--proficient CRC. Additionally, a subgroup of more aggressive N(0) tumors can be identified by evaluating vascular invasion and RKIP expression.
Subject(s)
Biomarkers, Tumor/analysis , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Neoplasm Invasiveness/pathology , Phosphatidylethanolamine Binding Protein/biosynthesis , Colorectal Neoplasms/mortality , DNA Mismatch Repair , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lymphatic Metastasis/pathology , Neoplasm Staging , Prognosis , Risk Factors , Sensitivity and Specificity , Survival Analysis , Tissue Array AnalysisABSTRACT
A roundtable consensus meeting was held to consolidate current knowledge on the etiology of colorectal cancer in patients with inflammatory bowel disease and to review current strategies, both diagnostic and preventive, specifically addressing the role of 5-aminosalicylic acid. Specific topics that were addressed included: the epidemiology of colorectal cancer, including an assessment of risk factors and the impact of colonoscopy on colorectal cancer incidence and mortality; the origin and evolution of dysplasia nomenclature and the natural history of dysplasia; review of the experience of St. Mark's Hospital (London) as gleaned from its surveillance database; mechanisms by which 5-aminosalicylic acid is thought to exert a chemopreventive effect; the potential future role of 5-aminosalicylic acid in chemopreventive strategies; chemoprevention in familial adenomatous polyposis; and other future research directions. This article provides a comprehensive overview of the issues discussed and should act as a guide to shaping the design of future studies in this area.