Serrated Polyposis: An Enigmatic Model of Colorectal Cancer Predisposition

Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps

Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation

BACKGROUND: We have previously reported activating mutations of the gene coding for the fibroblast growth factor receptor 3 (FGFR3) in invasive cervical carcinoma. To further analyze the role of FGFR3 in cervical tumor progression, we extended our study to screen a total of 75 invasive tumors and 80 cervical intraepithelial neoplasias (40 low-grade and 40 high-grade lesions). RESULTS: Using single strand conformation polymorphism (SSCP) followed by DNA sequencing, we found FGFR3 mutation (S249C in all cases) in 5% of invasive cervical carcinomas and no mutation in intraepithelial lesions. These results suggest that, unlike in bladder carcinoma, FGFR3 mutation does not or rarely occur in non invasive lesions. Compared to patients with wildtype FGFR3 tumor, patients with S249C FGFR3 mutated tumors were older (mean age 64 vs. 49.4 years, P = 0.02), and were more likely to be associated with a non-16/18 HPV type in their tumor. Gene expression analysis demonstrated that FGFR3 mutated tumors were associated with higher FGFR3b mRNA expression levels compared to wildtype FGFR3 tumors. Supervised analysis of Affymetrix expression data identified a significant number of genes specifically differentially expressed in tumors with respect to FGFR3 mutation status. CONCLUSION: This study suggest that tumors with FGFR3 mutation appear to have distinctive clinical and biological characteristics that may help in defining a population of patients for FGFR3 mutation screening

Identification of a Proliferation Gene Cluster Associated with HPV E6/E7 Expression Level and Viral DNA Load in Invasive Cervical Carcinoma

Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a Cervical Cancer Proliferation Cluster composed of 163 highly correlated transcripts, many of which corresponded to E2F pathway genes controlling cell proliferation, whereas no primary TP53 targets were present in this cluster. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P=0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus correspond to a biological marker useful for prognosis assessment and specific therapy of the disease

A morphological and molecular study of proposed early forms of the traditional serrated adenoma

AIMS: The traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognized, however, the origins of TSAs are not known and early forms have not been described. Some large TSAs present with a flat "shoulder" component surrounding the central protuberant component. We hypothesized that small polyps with the same histology as these "shoulder" regions may represent early TSAs. METHODS AND RESULTS: We collected 70 small (< 10mm) polyps that may represent early TSAs based on typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a "shoulder" component resembling these small polyps. The study polyps patients had a mean age of 58 years, 54% were female, had a mean 4.1mm diameter and were predominantly distal (71%). Morphologically, slit-like serration was present in 81%, ectopic crypt formations in 67% and a villous component in 47%. These histological features were similar to the 12 "shoulder" lesions. Immunohistochemical stains showed absence of β-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100% and Ki-67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps respectively. Compared with KRAS-mutated polyps, BRAF-mutated polyps were more likely to arise in a precursor polyp (82% vs 18%, P < 0.001) and were more likely to have slit-like serrations (100% vs 73%, P = 0.003). CONCLUSIONS: These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs and support the hypothesis that these polyps represent early forms of TSA. This article is protected by copyright. All rights reserved

Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans

Specific germline activating point mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) result in autosomal dominant human skeletal dysplasias. The identification in multiple myeloma and in two epithelial cancers—bladder and cervical carcinomas—of somatic FGFR3 mutations identical to the germinal activating mutations found in skeletal dysplasias, together with functional studies, have suggested an oncogenic role for this receptor. Although acanthosis nigricans, a benign skin tumor, has been found in some syndromes associated with germinal activating mutations of FGFR3, the role of activated FGFR3 in the epidermis has never been investigated. Here, we targeted an activated receptor mutant (S249C FGFR3) to the basal cells of the epidermis of transgenic mice. Mice expressing the transgene developed benign epidermal tumors with no sign of malignancy. These skin lesions had features in common with acanthosis nigricans and other benign human skin tumors, including seborrheic keratosis, one of the most common benign epidermal tumors in humans. We therefore screened a series of 62 cases of seborrheic keratosis for FGFR3 mutations. A large proportion of these tumors (39%) harbored somatic activating FGFR3 mutations, identical to those associated with skeletal dysplasia syndromes and bladder and cervical neoplasms. Our findings directly implicate FGFR3 activation as a major cause of benign epidermal tumors in human

Association between molecular subtypes of colorectal cancer and patient survival

BACKGROUND and AIMS: Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. METHODS: Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. RESULTS: Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. CONCLUSIONS: Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor. (C) 2014 Elsevier Inc. All rights reserved

Outcome in Advanced Ovarian Cancer following an Appropriate and Comprehensive Effort at Upfront Cytoreduction: A Twenty-Year Experience in a Single Cancer Institute

Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients. Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test. Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recurrence or death) were observed and 245 patients (72%) had died. The mortality and morbidity related to surgery were low. The main prognostic factor for overall survival was postoperative residual disease (P < .0002), while the main prognostic factor for disease-free survival was histological tumor type (P < .0007). Multivariate analysis identified three significant risk factors: optimal surgery (RR = 2.2 for suboptimal surgery), menopausal status (RR = 1.47 for postmenopausal women), and presence of a taxane in the chemotherapy combination (RR = 0.72). Conclusion. These results confirm that optimal surgery defined by an appropriate and comprehensive effort at upfront cytoreduction limits morbidity related to the surgical procedure and allows initiation of chemotherapy without any negative impact on survival. The impact of neoadjuvant chemotherapy to improve resectability while lowering the morbidity of the surgical procedure is discussed