Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.
To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.
Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.
All persons with newly diagnosed colorectal cancer and their relatives.
Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.
Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.
The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained.
The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years.
Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.
Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.
National Institutes of Health.
"Hereditary diseases are conditioned by small scale mutations (including point mutations and sequence changes concerning only few nucleotides such as small insertions, deletions, inversions) and the rearrangements of larger genome fragments known as copy number variations (CNVs) (Arlt et al. 2012; Beckmann et al. 2008; Hastings et al. 2009; Henrichsen et al. 2009). One of the challenges of contemporary molecular studies is the efficient and cost-effective detection of both types of changes in the genetic material (Ladabaum et al. 2011). The methods that are currently, widely used require separate analyses to detect small mutations and large rearrangements. "
[Show abstract][Hide abstract] ABSTRACT: Efficient and cost-effective screening for DNA sequence changes, both small mutations and copy number variations (CNVs), is a crucial aspect for routine genetic diagnostics as well as for basic research. In this study we present a development and evaluation of comparative-high resolution melting (C-HRM), a new approach for the simultaneous screening of small DNA changes and gene CNVs. In contrast to other methods, relative quantification in C-HRM is based on the results obtained during the melting process and calculations of the melting peak height ratio in the multiplex reaction. Validation of the method was conducted on DNA samples from 50 individuals from Duchenne muscular dystrophy (DMD) families, 50 probands diagnosed with familial adenomatous polyposis and a control group of 36 women and 36 men. The results of analyses conducted on fragments of the DMD and APC genes correspond completely (100 %) with the results of previous studies. C-HRM sensitivity in CNV detection was assessed through the analysis of mixed DNA samples with different proportions of a deletion carrier and wild type control. The results are presented as a linear regression with R2 of 0.9974 and imply the capability of the method to detect mosaics. C-HRM is an attractive and powerful alternative to other methods of point mutations and CNV detection with 100 % accuracy in our studied group.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1393-1) contains supplementary material, which is available to authorized users.
Human Genetics 11/2013; 133(5). DOI:10.1007/s00439-013-1393-1 · 4.82 Impact Factor
"Several centers have begun targeted screening for highly penetrant germline mutations for Lynch syndrome and in BRCA1/210,11,12 to identify genetically at-risk individuals. With appropriate immunohistochemical or other evidence suggestive of germline mutations, patients can be actively sought and counseled regarding the importance of genomic testing for their own treatment and for potential preventive care of their relatives. "
[Show abstract][Hide abstract] ABSTRACT: Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.
Genet Med 2013:15(4):258–267
Genetics in medicine: official journal of the American College of Medical Genetics 01/2013; 15(4). DOI:10.1038/gim.2012.157 · 7.33 Impact Factor
"In some hospitals, universal tumor testing has been implemented on all newly diagnosed CRCs and to a lesser extent, all newly diagnosed endometrial cancers, regardless of age at diagnosis or family history, in accordance with the EGAPP recommendations , which NSGC and CGA-ICC strongly support (EGAPP 2009; Mvundura et al. 2010). In these settings, a reduced cost testing approach is suggested, in which tumor testing with MSI or IHC analysis be performed, instead of MSI and IHC analyses together so that the process is cost-effective on a populationwide basis (Ladabaum et al. 2011). Although benefits and limitations between MSI and IHC analyses do exist, IHC can help target appropriate follow up tumor and germline testing when abnormal IHC is detected. "
[Show abstract][Hide abstract] ABSTRACT: Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.
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