Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.

BACKGROUND: Heterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS. METHODS: We report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5. RESULTS: Genomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis. CONCLUSION: Our results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of several genes belonging to the RAS Mitogen Activated Protein Kinase (MAPK) signaling pathway. Incontinentia Pigmenti (IP) is an X-linked, dominantly inherited multisystem disorder. CASE PRESENTATION: This study is the first report of the coexistence of Noonan (NS) and Incontinentia Pigmenti (IP) syndromes in the same patient. We report on the clinical phenotype and molecular characterization of this patient. The patient was examined by a pluridisciplinary staff of clinicians and geneticist. The clinical diagnosis of NS and IP was confirmed by molecular investigations. The newborn girl came to our clinics due to flagrant dysmorphia and dermatological manifestations. The clinical observations led to characterize the Incontinentia Pigmenti traits and a suspicion of a Noonan syndrome association. Molecular diagnosis was performed by Haloplex resequencing of 29 genes associated with RASopathies and confirmed the NS diagnosis. The common recurrent intragenic deletion mutation in IKBKG gene causing the IP was detected with an improved PCR protocol. CONCLUSION: This is the first report in the literature of comorbidity of NS and IP, two rare multisystem syndromes.

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As molecular diagnosis relying on Southern blot (SB) might be challenging in some cases, molecular combing (MC) was recently developed as an additional technique for FSHD diagnosis and exploration of the genomic organization of the 4q35 and 10q26 regions. In complement to the usual SB, we applied MC in a large cohort of 586 individuals with clinical FSHD. In 332 subjects, the two 4q alleles were normal in size, allowing exclusion of FSHD1 while we confirmed FSHD1 in 230 patients. In 14 patients from 10 families, we identified a recurrent complex heterozygous rearrangement at 4q35 consisting of a duplication of the D4Z4 array and a 4qA haplotype, irresolvable by the SB technique. In five families, we further identified variations in the SMCHD1 gene. Impact of the different mutations was tested using a minigene assay and we analyzed DNA methylation after sodium bisulfite modification and NGS sequencing. We discuss the involvement of this rearrangement in FSHD since all mutations in SMCHD1 are not associated with D4Z4 hypomethylation and do not always segregate with the disease.

Actionable Genes, Core Databases, and Locus-Specific Databases.

Adoption of next-generation sequencing (NGS) in a diagnostic context raises numerous questions with regard to identification and reports of secondary variants (SVs) in actionable genes. To better understand the whys and wherefores of these questioning, it is necessary to understand how they are selected during the filtering process and how their proportion can be estimated. It is likely that SVs are underestimated and that our capacity to label all true SVs can be improved. In this context, Locus-specific databases (LSDBs) can be key by providing a wealth of information and enabling classifying variants. We illustrate this issue by analyzing 318 SVs in 23 actionable genes involved in cancer susceptibility syndromes identified through sequencing of 572 participants selected for a range of atherosclerosis phenotypes. Among these 318 SVs, only 43.4% are reported in Human Gene Mutation Database (HGMD) Professional versus 71.4% in LSDB. In addition, 23.9% of HGMD Professional variants are reported as pathogenic versus 4.8% for LSDB. These data underline the benefits of LSDBs to annotate SVs and minimize overinterpretation of mutations thanks to their efficient curation process and collection of unpublished data.

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.

The UMD-APC database, a model of nation-wide knowledge base: update with data from 3,581 variations.

Familial adenomatous polyposis (FAP) is a rare autosomal-inherited disease that highly predisposes to colorectal cancer, characterized by a diffuse duodenal and colorectal polyposis associated with various extradigestive tumors and linked to germline mutations within the APC gene. A French consortium of laboratories involved in APC mutation screening has progressively improved the description of the variation spectrum, inferred functional significance of nontruncating variations, and delineated phenotypic characteristics of the disease. The current version of the UMD-APC database is described here. The total number of variations has risen to 5,453 representing 1,473 distinct variations. The published records initially registered into the database were extended with 3,581 germline variations found through genetic testing performed by the eight licensed laboratories belonging to the French APC network. Sixty six of 149 variations of previously unknown significance have now been classified as (likely) causal or neutral. The database is available on the Internet (http://www.umd.be/APC/) and updated twice per year according to the consensus rules of the network. The UMD-APC database is thus expected to facilitate functional classification of rare synonymous, nonsynonymous, and intronic mutations and consequently improve genetic counseling and medical care in FAP families.

High-resolution analysis of DNA copy number alterations in rectal cancer: correlation with metastasis, survival, and mRNA expression.

BACKGROUND AND PURPOSE: This study aimed to determine the candidate genes and chromosomal imbalances capable of predicting occurrences of metastasis in patients with rectal cancer. PATIENTS AND METHODS: Fresh frozen tumor tissues from 80 patients with rectal cancer were prospectively collected and analyzed using Affymetrix HG-U133 Plus 2.0 gene expression arrays and high-resolution Illumina single-nucleotide polymorphism (SNP) arrays. Endpoints of the study were metastasis-free survival (MFS) and cancer-specific survival (CSS). RESULTS: The median follow-up was 102 months (1-146). Deletions of 8p and 1p36-35 correlated with worse MFS (p = 0.005 and p = 0.01, respectively) and CSS (p = 0.001 and p = 0.01, respectively). Multivariate analysis identified 8p deletion as an independent prognostic factor for MFS (p = 0.04) and CSS (p = 0.003); 97 genes located on the 8p chromosome were significantly underexpressed in tumors with 8p deletion. CONCLUSION: This study shows for the first time in rectal cancer an independent correlation of 8p deletion with MFS and CSS and highlights potential new tumor suppressor genes.

Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.

BACKGROUND: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses. METHODS AND FINDINGS: Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CC phenotype-like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II-III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1-2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available. CONCLUSIONS: We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways.

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.

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial.

Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A, VEGF receptors (VEGFR-1, VEGFR-2), and hypoxia inducible factor-1α (HIF-1α) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype (n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7-17.1)] (p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1-42.8) versus 22.5 (95% CI: 18.6-24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2-11.3) versus 9.2 (95% CI: 8.71-10.1)], and duration of the first CFI [4.6 (95% CI: 1.6-13.3) versus 4.14 (95% CI: 0.5-29.0) months, p = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.

Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

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.)

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

We propose a formal statistical inference framework for the evaluation of the penetrance of a rare genetic mutation using family data generated under a kin-cohort type of design, where phenotype and genotype information from first-degree relatives (sibs and/or offspring) of case probands carrying the targeted mutation are collected. Our approach is built upon a likelihood model with some minor assumptions, and it can be used for age-dependent penetrance estimation that permits adjustment for covariates. Furthermore, the derived likelihood allows unobserved risk factors that are correlated within family members. The validity of the approach is confirmed by simulation studies. We apply the proposed approach to estimating the age-dependent cancer risk among carriers of the MSH2 or MLH1 mutation.

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

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

Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP.

Heterozygous APC germline alteration is responsible for familial adenomatous polyposis, a colon cancer predisposition with almost complete penetrance. Point mutations generally lead to truncated proteins or no protein at all. They mainly involve exon 3 to codon 1700 (exon 15). The work presented here delineates precisely the APC mutation spectrum from 15 years of systematic molecular screening which identified 863 independent alterations in the French population.

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

CONTEXT: Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE: To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS: Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE: Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS: Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS: MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.

Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the MDM2 and CDK4 genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies targeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarcomas.