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Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.

ABSTRACT: To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.

SUBMITTER: Hwang SJ

PROVIDER: S-EPMC1180359 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.

Hwang Shih-Jen SJ Lozano Guillermina G Amos Christopher I CI Strong Louise C LC

American journal of human genetics 20030227 4

To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include ...[more]

PMID: 12610779

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Project description:BackgroundEndometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study.MethodsWe selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided.ResultsFifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%).ConclusionsBRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

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Project description:Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

Dataset Information

Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.

Publications

Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.

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