Germline MUTYH gene mutations are not frequently found in unselected patients with papillary breast carcinoma.

MUTYH-associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.

Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients.

BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. METHODS: Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. RESULTS: Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. CONCLUSIONS: Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

e-Learning for Instruction and to Improve Reproducibility of Scoring Tumor-Stroma Ratio in Colon Carcinoma: Performance and Reproducibility Assessment in the UNITED Study.

BACKGROUND: The amount of stroma in the primary tumor is an important prognostic parameter. The tumor-stroma ratio (TSR) was previously validated by international research groups as a robust parameter with good interobserver agreement. OBJECTIVE: The Uniform Noting for International Application of the Tumor-Stroma Ratio as an Easy Diagnostic Tool (UNITED) study was developed to bring the TSR to clinical implementation. As part of the study, an e-Learning module was constructed to confirm the reproducibility of scoring the TSR after proper instruction. METHODS: The e-Learning module consists of an autoinstruction for TSR determination (instruction video or written protocol) and three sets of 40 cases (training, test, and repetition sets). Scoring the TSR is performed on hematoxylin and eosin-stained sections and takes only 1-2 minutes. Cases are considered stroma-low if the amount of stroma is ≤50%, whereas a stroma-high case is defined as >50% stroma. Inter- and intraobserver agreements were determined based on the Cohen κ score after each set to evaluate the reproducibility. RESULTS: Pathologists and pathology residents (N=63) with special interest in colorectal cancer participated in the e-Learning. Forty-nine participants started the e-Learning and 31 (63%) finished the whole cycle (3 sets). A significant improvement was observed from the training set to the test set; the median κ score improved from 0.72 to 0.77 (P=.002). CONCLUSIONS: e-Learning is an effective method to instruct pathologists and pathology residents for scoring the TSR. The reliability of scoring improved from the training to the test set and did not fall back with the repetition set, confirming the reproducibility of the TSR scoring method. TRIAL REGISTRATION: The Netherlands Trial Registry NTR7270; https://www.trialregister.nl/trial/7072. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/13464.

Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies.

Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Acquiring experience in pathology predominantly from what you see, not from what you read: the HIPON e-learning platform.

It is indisputable that nowadays one of the hardest and most important tasks in medicine and especially in medical education, is the conversion of the extensive amount of available data, into medical experience, after a proper analysis. A project under the title "ICT (Information and Communication Technology) eModules on HistoPathology: a useful online tool for students, researchers and professionals - HIPON", co-financed by the Lifelong Learning Program of the Education, Audiovisual and Culture Executive Agency (EACEA), The Commission of the European Union, has been launched at the beginning of 2013. HIPON's purpose is not to provide just another pathology website atlas, but to convey professional experience and thinking in pathology. HIPON has resulted in a well-structured and user-friendly, open resource, multi-language, e-learning platform which, taking advantage of modern image technology, offers medical students, researchers, and professionals a valuable teaching instrument so that they can acquire professional experience in pathology. The mid-term report of HIPON has been favorably evaluated by the EACEA experts who appreciated the potential of our teaching tool in providing the opportunity and the means to acquire medical experience. Through the use of virtual slides, educative videos and microscopic, high resolution, marked images accompanied by relevant questions and answers, HIPON project aims to make end-users able to think as experienced pathologists and become highly efficient in correlating pathologic data with other clinical-laboratory information.

Familial gastric cancer: detection of a hereditary cause helps to understand its etiology.

Worldwide, gastric cancer is one of the most common forms of cancer, with a high morbidity and mortality. Several environmental factors predispose to the development of gastric cancer, such as Helicobacter pylori infection, diet and smoking. Familial clustering of gastric cancer is seen in 10% of cases, and approximately 3% of gastric cancer cases arise in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at relatively young age. Germline mutations in the CDH1 gene are the major cause of HDGC and are identified in approximately 25-50% of families which fulfill strict criteria. Prophylactic gastrectomy is the only option to prevent gastric cancer in individuals with a CDH1 mutation. However, in the majority of families with multiple cases of gastric cancer no germline genetic abnormality can be identified and therefore preventive measures are not available, except for general lifestyle advice. Future research should focus on identifying new genetic predisposing factors for all types of familial gastric cancer.