The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to ...define the cancer risk faced by PMS2 mutation carriers.
Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.
The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.
CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, ...MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.
ABSTRACT
Mutation detection through exome sequencing allows simultaneous analysis of all coding sequences of genes. However, it cannot yet replace Sanger sequencing (SS) in diagnostics because of ...incomplete representation and coverage of exons leading to missing clinically relevant mutations. Targeted next‐generation sequencing (NGS), in which a selected fraction of genes is sequenced, may circumvent these shortcomings. We aimed to determine whether the sensitivity and specificity of targeted NGS is equal to those of SS. We constructed a targeted enrichment kit that includes 48 genes associated with hereditary cardiomyopathies. In total, 84 individuals with cardiomyopathies were sequenced using 151 bp paired‐end reads on an Illumina MiSeq sequencer. The reproducibility was tested by repeating the entire procedure for five patients. The coverage of ≥30 reads per nucleotide, our major quality criterion, was 99% and in total ∼21,000 variants were identified. Confirmation with SS was performed for 168 variants (155 substitutions, 13 indels). All were confirmed, including a deletion of 18 bp and an insertion of 6 bp. The reproducibility was nearly 100%. We demonstrate that targeted NGS of a disease‐specific subset of genes is equal to the quality of SS and it can therefore be reliably implemented as a stand‐alone diagnostic test.
A NGS stand‐alone diagnostic test for hereditary cardio‐myopathies. Parallel analyses of 48 genes on a MiSeq identified ∼21,000 variants in 84 patients. The sensitivity and specificity of this test equals Sanger Sequencing. In total 168 variants were confirmed, no false‐positives or false‐negatives were detected.
Most patients with
gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists ...with respect to cancer risk and survival.
This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in
carriers up to 75 years of age.
3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_
, path_
and path_
carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%.
carriers had lower risk for cancer.
Carriers of different
variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and
variant. We have updated our open-access website www.lscarisk.org to facilitate this.
Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to ...provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6.
Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk.
The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers.
The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to ...as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder.
ABSTRACT
We have developed a tool for detecting single exon copy‐number variations (CNVs) in targeted next‐generation sequencing data: CoNVaDING (Copy Number Variation Detection In Next‐generation ...sequencing Gene panels). CoNVaDING includes a stringent quality control (QC) metric, that excludes or flags low‐quality exons. Since this QC shows exactly which exons can be reliably analyzed and which exons are in need of an alternative analysis method, CoNVaDING is not only useful for CNV detection in a research setting, but also in clinical diagnostics. During the validation phase, CoNVaDING detected all known CNVs in high‐quality targets in 320 samples analyzed, giving 100% sensitivity and 99.998% specificity for 308,574 exons. CoNVaDING outperforms existing tools by exhibiting a higher sensitivity and specificity and by precisely identifying low‐quality samples and regions.
We have developed a tool for detecting single exon copy number variations (CNVs) in targeted next‐generation sequencing data: CoNVaDING (Copy Number Variation Detection In Next‐generation sequencing Gene panels). CoNVaDING includes a stringent quality control metric, that excludes or flags low quality exons. Since this quality control shows exactly which exons can be reliably analysed and which exons are in need of an alternative analysis method, CoNVaDING is also useful for CNV detection in clinical diagnostics.
We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of ...allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines. It can be found at http://molgenis.org/gavin .
BACKGROUND Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, ...TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. METHOD A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records. RESULTS A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. CONCLUSION We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.
Summary Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2–3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, ...including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin cancer. In this Review, we discuss the risks, surveillance tests, and guidelines for the management of extracolonic tumours associated with Lynch syndrome. For all types of extracolonic cancer, evidence supporting surveillance is scarce. A benefit of surveillance is evident only for endometrial cancer, where transvaginal ultrasound and endometrial sampling detect tumours in early stages. Surveillance is generally recommended for urinary tract and gastric cancer, especially in families with more than one member with these types of cancer. For the other types of cancer, surveillance is typically not recommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be considered for women with Lynch syndrome who are past childbearing age, especially during surgery for colorectal cancer. No data show efficacy of chemopreventive drugs in reducing the risk of extracolonic cancers for patients with Lynch syndrome.
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