Modeling of successive cancer risks in Lynch syndrome families in the presence of competing risks using copulas.
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ABSTRACT:
SUBMITTER: Choi YH
PROVIDER: S-EPMC5319907 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Modeling of successive cancer risks in Lynch syndrome families in the presence of competing risks using copulas.
Choi Yun-Hee YH Briollais Laurent L Win Aung K AK Hopper John J Buchanan Dan D Jenkins Mark M Lakhal-Chaieb Lajmi L
Biometrics 20160705 1
In this article, we propose an association model to estimate the penetrance (risk) of successive cancers in the presence of competing risks. The association between the successive events is modeled via a copula and a proportional hazards model is specified for each competing event. This work is motivated by the analysis of successive cancers for people with Lynch Syndrome in the presence of competing risks. The proposed inference procedure is adapted to handle missing genetic covariates and sele ...[more]
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Project description:BackgroundThe risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families.MethodsIn this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes).ResultsWe found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively.ConclusionsIndividuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.
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Project description:Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype. In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect inferential conclusions. We compare the fit of four-candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding effect of changes in secular trends, screening, and medical practices that may affect time to disease detection across birth cohorts. Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts. Our motivating case study comes from a Danish cancer register of 124 families with mutations in mismatch repair (MMR) genes known to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families.
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Project description:BACKGROUND:Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population. METHODS:Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX. RESULTS:The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX. CONCLUSIONS:The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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Project description:Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.
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Project description:Objectives:
Specific Aims:
1. Researchers will evaluate and compare predictors of health-related quality of life (QOL) among colorectal cancer (CRC) survivors who have Lynch syndrome (LS) with those patients who have sporadic CRC using both quantitative and qualitative methodology.
a. In both CRC groups, researchers will evaluate cancer preventive and health behaviors, including lifestyle factors and screening, psychosocial factors, including mood, family functioning, coping style, anxiety, depression, and social resources, and health care system factors, including interactions with health care providers and service utilization.
2. Researchers will compare the experience of first-degree relatives (FDRs) of patients who have LS with that of FDRs of patients who have sporadic CRC using both quantitative and qualitative methodology.
a. Researchers will evaluate all of the domains listed above, as well as anticipatory grief, assessment of caregiving responsibilities, and fear of cancer in FDRs of patients with LS-related and sporadic CRC.
3. Researchers will examine CRC patients from both groups and their FDRs using dyadic analyses in order to evaluate the similarities and differences in their survivorship experience.
4. Researchers will evaluate the preventive and health behavior of patients who are non-conclusive for Lynch syndrome and their family members. They will examine their screening behavior and will explore how the interaction between the patients and their relatives affects the relatives’ screening behavior. They also will examine how these non conclusive LS patients and their family members perceive their risk for LS-related cancers.
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