Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

Endoscopic findings in Cowden syndrome.

Cowden syndrome is characterized by diffuse hamartomas involving the whole digestive tract. The gastrointestinal expression of the disease is inconstant, but hamartomatous polyposes are frequent. In a multicenter study we studied the endoscopic appearance of Cowden syndrome--as defined by fulfillment of international consortium criteria--in 10 patients. In 6 of the 10 patients the connection with Cowden syndrome was made retrospectively on the basis of the gastrointestinal endoscopic findings. All patients had upper and lower gastrointestinal tract involvement. Mean follow-up duration was 9.5 years (range: 2-26 years). Mean age was 37 years (range: 18-56 years). Polyps of the upper gastrointestinal tract were hamartomas, ganglioneuromas, lipomas, and adenomas. Diffuse glycogenic acanthosis was reported in nine patients. Besides the classical hamartomatous polyposis, diffuse macroscopic esophageal acanthosis and microscopic ganglioneuromatosis are other key findings associated with a diagnosis of Cowden syndrome. Physicians should be aware of these characteristics in order to diagnose Cowden syndrome early.

Application of ANAES guidelines for colonoscopy in France: a practical survey.

OBJECTIVES: In 2004, the French health authorities published guidelines on the indications for colonoscopy. However, no study has evaluated the awareness of healthcare practitioners of these guidelines. The aim of this study was to determine the level of awareness of the ANAES guidelines among French gastroenterologists. PATIENTS AND METHODS: A questionnaire comprising 20 multiple choice questions (MCQ) was presented to a group of 79 gastroenterologists between February and June in 2008. The questions covered screening tests for colon cancer (one question), endoscopic mucosal resection (two questions) and the ANAES guidelines (17 questions). According to the number of colonoscopies performed per year (less than 100, 100-500, more than 500), the answers to these questions were analyzed separately. RESULTS: Among the practitioners carrying out less than 100, 100-500 and more than 500 colonoscopies per year, the guidelines for colon cancer screening were known by 33, 50 and 56%, respectively, the quality criteria for endoscopic mucosal resection by 0, 0 and 3.7%, respectively, and the ANAES guideline indications for colonoscopy by 34.3, 51.2 and 48.9%, respectively (P<0.001). The ANAES guidelines were significantly better known by practitioners who were performing more than 100 colonoscopies per year, while the indications for control colonoscopy were less often correctly anticipated. No differences were found concerning postponed indications. CONCLUSION: The ANAES guidelines consists of the following elements: (1) awareness of the ANAES guidelines is poor, with control colonoscopy being correctly anticipated in just over a third of the gastroenterologists; (2) performing more than 100 colonoscopies per year improves knowledge of the ANAES guidelines; and (3) the ANAES guidelines need to be simplified and should be covered by continuing medical education.

Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability.

Accumulation of frameshift mutations at genes containing coding mononucleotide repeats is thought to be the major molecular mechanism by which mismatch repair-deficient cells accumulate functional alterations. These mutations resulting from microsatellite instability (MSI) can affect genes involved in pathways with a putative oncogenic role, but may also arise in genes without any expected role in MSI carcinogenesis because of the high mutation background of these tumours. We here screened 39 MSI colorectal tumours for the presence of mutations in 25 genes involved in DNA damage signalling and repair pathways. Using a maximum likelihood statistical method, these genes were divided into two different groups that differed significantly in their mutation frequencies, and likely represent mutations that do or do not provide selective pressure during MSI tumour progression. Interestingly, the so-called real-target mutational events were found to be distributed among genes involved in different functional pathways of the DNA metabolism, for example, DNA damage signalling (DNA-PKcs, ATR), double-strand break (DSB) repair (DNA-PKcs, RAD50), mismatch repair (MSH3, MSH6, MBD4) and replication (POLD3). In particular, mutations in MRE11 and/or RAD50 were observed in the vast majority of the tumours and resulted in the concomitant loss of immunohistochemical expression of both proteins. These data might explain why MSI colorectal cancers (CRC) behave differently in response to a wide variety of chemotherapeutic agents, notably those targeting DNA. More generally, they give further insights into how MSI leads to functional changes with synergistic effects in oncogenic pathways.

[Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas]. / Identification et prise en charge du syndrome HNPCC (hereditary non polyposis colon cancer). Prédisposition héréditaire aux cancers du côlon, du rectum et de l'utérus.

BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.

[HNPCC syndrome (hereditary non polyposis colon cancer): identification and management]. / Le syndrome HNPCC (hereditary non polyposis colon cancer): identification et prise en charge.

BACKGROUND: The hereditary non-polyposis colon cancer (HNPCC) syndrome is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for other organs tumors. HNPCC syndrome is responsible for 5% of colorectal cancers. MAJOR ASPECTS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a two-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. FURTHER DEVELOPMENTS: The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks; other organs being at low lifetime risk, no specific surveillance will be proposed.

[Practical data on digestive tract oncogenetics]. / Données pratiques en Oncogénétique digestive.

Inherited conditions predisposing to cancers have long been recognized. Specific medical recommendations have more recently been proposed to avoid the development of advanced cancers in such high-risk families. The identification of the first genes involved in monogenic dominant cancer-prone conditions have opened the ways to their predictive diagnosis in asymptomatic members in at-risk families. The development of such procedures has required specific involvement for clinicians and molecular geneticians. The example of familial predispositions to colonic cancers has been chosen to illustrate the practical issues, and to help the physicians in charge of at-risk families to offer their patients an access to these emerging possibilities in cancer prevention. A table summarizes the practical issues requested to refer a family and initiate the procedure of molecular testing.

Extensive molecular screening for hereditary non-polyposis colorectal cancer.

The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFbetaRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria (n = 10), families in which at least one of the criteria was not satisfied (n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 (n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases.

[Muir-Torre syndrome and familial colorectal cancer: 2 families with molecular genetic analysis]. / Syndrome de Muir-Torre et cancer colorectal familial: deux familles avec étude génétique moléculaire.

INTRODUCTION: The Muir-Torre Syndrome is a rare genodermatosis, defined by the occurrence of cutaneous tumors (such as sebaceous adenomas, epitheliomas, or carcinomas, and/or keratoacanthomas), and internal malignancies. Recently, molecular analysis in hereditary non polyposis colorectal cancer demonstrated a common genetic basis, linking these two disorders, with the observation of germline mutations in the hMSH2 gene (one of the DNA mismatch repair system genes) in both syndromes. Such molecular demonstration of a single nosological entity should be clinically used to improve the indications of molecular testings in oncogenetics, still restricted to highly stringent criteria for hereditary non polyposis colorectal cancer. CLINICAL CASES: We identified three patients from two different families, who fulfilled the criteria for both Muir-Torre Syndrome and hereditary non polyposis colorectal cancer. The search of a germline mutation of the hMSH2 gene was performed on an affected member from each family, and their relatives with their informed consent. Within each family, all individuals with colorectal cancer were carriers of the same mutation. In the first family, this mutation was a pathogenic microinsertion, usable for predictive testing. In the second family, a missense mutation was identified, requesting further demonstration of its pathogenicity before its use in a predictive purpose. CONCLUSIONS: The diagnosis of cutaneous tumors compatible with Muir-Torre syndrome should lead the dermatologist to suspect an hereditary non polyposis colorectal cancer that should bring to an oncogenetic approach: personnal and familial history of colorectal cancer, molecular analysis, recommendations for colonoscopic screening in at-risk relatives. In the case of a colorectal cancer at a young age, or in the case of familial cases, the gastroenterologist should screen for cutaneous lesions of Muir-Torre syndrome, which could add a criteria for an hereditary syndrome, and lead to molecular oncogenetic analysis.

5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer.

The aim of this Phase III, balanced randomised trial was to compare continuous intravenous infusion (CVI) of 5-FU with bolus (B) administration for metastatic colorectal cancer (CRC). One hundred and fifty-five non-pretreated patients were randomised to receive CVI 5-FU at a dose of 750 mg/m2/day (d), 7 d every 21 d (n = 77), or bolus 5-FU 500 mg/m2/d x 5 d every 28 d (n = 78). Incremental dose escalation at 50 mg per step was recommended in the absence of toxicity. All the patients had measurable metastatic disease (M), particularly, liver and a good performance status (WHO grade 0-1). Dose intensity was significantly higher in CVI than in the bolus group: 1369 mg/m2/week versus 558 mg/m2/week (P = 0.0001). Grade II-IV stomatitis was more frequent in the CVI group (31% versus 9%; P < 0.0001) as was hand and foot syndrome (14% versus 3%; P < 0.001). Diarrhoea (22% versus 12%) and grade III granulocytopenia (2% versus 6%) were comparable. Responses were more frequent in the CVI (26%) than in the bolus group (13%) (P < 0.04); progression-free survival was higher for the CVI group (P = 0.04), but there was no statistical difference in overall survival (median: 10 months (m) compared to 9 m), and 1 year survival (SD) 42% (6%) versus 40% (6%). In the multivariate analysis, survival was better for patients with a good PS, well-differentiated adenocarcinomas and a primary tumour without serosal extension. In conclusion, with a higher dose intensity, CVI 5-FU improved tumour control, but not overall survival.

Nonsteroidal anti-inflammatory drug-induced colonic strictures: two cases and literature review.

We report two patients with large bowel submucosal diaphragm disease associated with nonsteroidal anti-inflammatory drugs (slow release form of diclofenac and phenylbutazone) who were admitted in 1990 and 1991 because of iron deficiency. At colonoscopy, the lumen of the ascending colon was divided into compartments by multiple thin circumferential mucosal membranes. Barium enema showed two short strictures in one patient. Right hemicolectomy was carried out on one patient. The other patient was simply advised to discontinue taking diclofenac and remains well. Such lesions are rare (10 cases have been reported) and resemble those previously described in the small bowel.

Carcinomas of the colon with multidirectional differentiation. Report of two cases and review of the literature.

Two cases of colonic carcinomas with multidirectional differentiation are presented. Both tumors showed light microscopic and immunohistochemical evidence of areas of adenocarcinomatous, squamous cell carcinomatous, and neuroendocrine differentiation. Only six similar cases have been previously reported. These highly malignant tumors support the recent concept of a multipotential stem cell within the mucosa of the gastrointestinal tract capable of differentiation in several directions.

[Colorectal cancers at the time of molecular genetics]. / Cancers colo-rectaux à l'heure de la génétique moléculaire.

One must always keep in mind the distinction between constitutional genetic mutation and acquired or somatic genetic mutation. Our knowledge of the syndromes resulting from germ line mutations and the detailed clinical description of the diseased patients have been the key to research into the field of susceptibility to colorectal cancer. Research has now entered a new era due two major advances. First it is now possible to identify persons at risk, carriers of constitutional defects involving genes responsible for colorectal cancer. Secondly, it is now possible to better identify high risk lesions based on histological examination and use of molecular markers. In the future, further progress will allow us to analyse acquired mutations. These advances open the way to new diagnostic approaches and raise a considerable number of questions concerning the ethics of molecular diagnosis and treatment.