iCOMET, national research project on genes predisposing to the development of metastases in patients treated for sporadic stage II colon cancer

Le cancer colorectal est, par sa fréquence et sa gravité, un problème de Santé publique. Le risque au cours de la vie est de 4 %, et la survie après intervention chirurgicale de 50 % à 5 ans malgré l’évolution des chimiothérapies adjuvantes et l’utilisation de drogues ciblées. En cas de cancer colique de stade II, soit un tiers des patients, la chimiothérapie adjuvante n’est pas habituellement proposée alors que plus de 20 % développent une maladie métastatique. L’étude de la carcinogenèse a révélé plusieurs voies, en faible proportion favorisées par la constitution génétique, faisant intervenir des mutations somatiques sur de multiples gènes, notamment l’inactivation alternative de gènes suppresseurs de tumeurs (APC et MMR) et l’activation de l’oncogène KRAS dans les étapes d’initiation, l’inactivation somatique des voies p53 et TGFB dans la transformation maligne des adénomes. Aucune altération génétique acquise n’a cependant été associée de manière certaine à l’évolution pronostique, à l’exception de l’inactivation du gène APC dont l’explication biologique est peu documentée. Le processus métastatique est cependant un élément décisif de l’évolution tumorale déterminé précocement. Une petite dizaine de syndromes de prédisposition majeure au cancer a été identifiée qui rend compte d’environ un tiers des agrégations familiales ou individuelles. Récemment, grâce à des consortiums d’études internationaux, 5 locus de susceptibilité mineure ont été identifiés par des études d’associations qui renforcent l’évidence d’une hérédité complexe. Si le processus métastatique est également prédéterminé, cette prédisposition génétique s’exprimera en cas de développement d’un cancer colique ; et une recherche d’associations, chez des patients dont le pronostic du cancer colique n’est pas lié à une extension locorégionale de la tumeur (localisation intra-péritonéale sans envahissement ganglionnaire au diagnostic), doit documenter cette hypothèse. La recherche proposée ici, en étroite collaboration avec l’ensemble des associations de professionnels impliqués dans la prise en charge des cancers coliques, permettra de définir les locus de prédisposition au développement de métastases et leur degré d’implication, et donc de proposer des tests préthérapeutiques simples identifiant le risque individuel en complément de l’analyse histologique. Cette ressource biologique et informatique dont la qualité aura été rigoureusement contrôlée, pilotée par un conseil scientifique indépendant, pourra bénéficier aux projets que souhaiteront développer d’autres équipes de recherche, et aux consortiums internationaux d’études d’associations.Colorectal cancer is a major problem in Western countries, leading to national recommendations for systematic screening of the general population. It is associated with therapeutic challenges too, 50% of patients dying within 5 years after diagnosis, despite regular progress in the adjuvant chemotherapy protocols and the use of targeted drugs. To date, it is not recommended to enter systematically stage II colon cancer patients (30% of cases) in adjuvant chemotherapy protocols, although more than 20% will develop distant metastases. Genetic mechanisms underlying carcinogenesis have been extensively studied since 20 years and several pathways alternatively inactivated through biallelic alteration of tumor suppressor genes (APC, MMR) and acquired mutations of the KRAS oncogene have been identified. Somatic inactivation of p53 and TGFB pathways have been associated with the acquisition of malignant characteristics in adenomas. No genetic alteration has been undoubtedly found to be linked to the prognosis, except APC mutations that are presently strong but unexplained predictors of the metastatic risk. It turns out now to be highly believable that metastatic process takes place very early in tumorigenesis. Early mechanisms of colorectal tumorigenesis are accelerated when genes involved in the initiation steps are mutated in the germline, as explaining several major predispositions to cancer, that account for one third of familial or individual colorectal tumors aggregations. At present, international consortiums allowed to identify 5 susceptibility loci through genome wide association studies (GWAS), which enforce the hypothesis of a complex heredity that progressively emerged these past years. We think that the metastatic risk is also genetically determined, this predisposition being observable only in case of colorectal cancer. No familial approach being relevant to address this question, association studies have to be performed in a priori good prognosis colon cancer patients (without risk of regional progression, i.e. lymph nodes metastases). A national consortium of surgeons, oncologists, gastroenterologists and pathologists has been set up and should let to recruit 7,800 stage II colon cancer patients within 4 years, one third presenting distant metastases. These patients will be asked for a blood sample. Medical data will be electronically registered through a dedicated and normalized format with the help of a specialized CRO. Blood samples will be proceeded in a Biological Resource Canter and CNG will be asked for genotyping. Tumor samples will be selected by pathologists on fixed tissues. Statistical analyses will be performed with the CRO (descriptive analyses) and we will conduct GWAS with teams specialized in the search for susceptibility loci associated with colorectal cancer risk, focussing first on genes known to be involved in colorectal cancer pathways. The present project will allow to define loci involved in the metastatic risk and to propose simple pre-therapeutic tests to determine the individual risk of developing metastases, thus improving the histologic staging, the only parameter to take place in the therapeutic decision to date. This national biologic and electronic resource will be supervised by an independent scientific committee to facilitate interactions with current and future projects developed by other teams as well as international genome-wide association studies

Semiparametric inference on the penetrances of rare genetic mutations based on a case-family design

A formal semiparametric statistical inference framework is proposed for the evaluation of the age-dependent penetrance of a rare genetic mutation, using family data generated under a case-family design, where phenotype and genotype information are collected from first-degree relatives of case probands carrying the targeted mutation. The proposed approach allows for unobserved risk factors that are correlated among family members. Some rigorous large sample properties are established, which show that the proposed estimators were asymptotically semi-parametric efficient. A simulation study is conducted to evaluate the performance of the new approach, which shows the robustness of the proposed semiparamteric approach and its advantage over the corresponding parametric approach. As an illustration, the proposed approach is applied to estimating the age-dependent cancer risk among carriers of the MSH2 or MLH1 mutation

8q24 Cancer Risk Allele Associated with Major Metastatic Risk in Inflammatory Breast Cancer

BACKGROUND: Association studies have identified low penetrance alleles that participate to the risk of cancer development. The 8q24 chromosomal region contains several such loci involved in various cancers that have been recently studied for their propensity to influence the clinical outcome of prostate cancer. We investigated here two 8q24 breast and colon cancer risk alleles in the close vicinity of the MYC gene for their role in the occurrence of distant metastases. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective series of 449 patients affected with breast or colon adenocarcinoma was genotyped for the rs13281615 and/or rs6983267 SNPs. Statistical analyses were done using the survival package v2.30 in the R software v2.9.1. The two SNPs did not influence the development of distant metastases of colon cancer; rs6983267 showed a mild effect on breast cancer. However, this effect was greatly emphasized when considering inflammatory breast cancer (IBC) solely. Replicated on a larger and independent series of IBC the contribution of the genotype to the metastatic risk of IBC was found an independent predictor of outcome (p = 2e-4; OR 8.3, CI95:2.6-33). CONCLUSIONS/SIGNIFICANCE: Our study shows first that the monitoring of this specific germline variation may add a substantial tool for IBC prognostication, an aggressive disease that evolves towards distant metastases much more frequently than non-IBC and for which no reliable prognostic factor is available in medical practice. Second, it more generally suggests that risk alleles, while associated with low susceptibility, could correlate with a high risk of metastasis

SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis

<p>Abstract</p> <p>Background</p> <p>Schwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic <it>NF2 </it>mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the <it>SMARCB1 </it>(<it>INI1</it>) tumor suppressor gene were described in familial and sporadic schwannomatosis patients.</p> <p>Methods</p> <p>To delineate the <it>SMARCB1 </it>gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas.</p> <p>Results</p> <p>Nine variants scattered along the sequence of <it>SMARCB1 </it>were identified. Five of them were classified as deleterious. All five patients carrying a <it>SMARCB1 </it>mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age.</p> <p>Conclusions</p> <p>These results suggest that patients with schwannomas have a significant probability of carrying a <it>SMARCB1 </it>mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the <it>SMARCB1 </it>gene.</p

A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

International audienceBackground: Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity.Methods: We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced.Results: Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients.Conclusion: This preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit

Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias

<p>Abstract</p> <p>Background</p> <p>Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation.</p> <p>Methods</p> <p>We searched for mutations in the <it>ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 </it>and <it>WT1 </it>genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype.</p> <p>Results</p> <p>Mutations in <it>ASXL1 </it>and <it>CBL </it>were frequent in refractory anemia with excess of blasts. Mutations in <it>TET2 </it>occurred with similar frequency in MDSs and AMLs and associated equally with either <it>ASXL1 </it>or <it>NPM1 </it>mutations. Mutations of <it>RUNX1 </it>were mutually exclusive with <it>TET2 </it>and combined with <it>ASXL1 </it>but not with <it>NPM1</it>. Mutations in <it>FLT3 (</it>mutation and internal tandem duplication), <it>IDH1</it>, <it>IDH2</it>, <it>NPM1 </it>and <it>WT1 </it>occurred primarily in AMLs.</p> <p>Conclusion</p> <p>Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.</p

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Vers un traitement individualisé du cancer Colorectal

Pour un laboratoire comme Amgen, l’identification de molécules apportant un bénéfice thérapeutique dans les cancers solides ou en hématologie est un enjeu majeur. C’est pourquoi depuis sa création, Amgen s’est engagé à donner la priorité aux recherches les plus innovantes et investit chaque année plus de 20 % de son chiffre d’affaires en Recherche et Développement