Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma.
ABSTRACT Purpose:Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied.Patients and Methods:A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons.Results:Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45.Conclusions:Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.
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ABSTRACT: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.Journal of Clinical Pathology 07/2014; · 2.55 Impact Factor
- Journal of Clinical Oncology 02/2014; · 17.88 Impact Factor
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ABSTRACT: The Li-Fraumeni tumor syndrome is strongly associated with adrenocortical carcinoma (ACC), and caused by germline mutations in TP53 in 70% of cases. Also, TP53 polymorphisms have been shown to influence both cancer risk and clinical outcome in several tumor entities. We, therefore, investigated TP53 polymorphisms in a cohort of adult patients with ACC. Evaluation of the role of TP53 polymorphisms in adult patients with ACC. Peripheral blood for DNA extraction was collected from 72 ACC patients. Polymorphism analysis was performed by amplification and sequencing of exons and adjacent intron sections of TP53. Results were correlated with clinical data and the distribution of the polymorphisms was compared to published Caucasian control groups. Compared to control groups, genotype frequencies of analyzed TP53 polymorphisms amongst ACC patients were significantly different in 3 out of 4 polymorphisms: IVS2+38G>C (G/G, p=0.0248), IVS3ins16 (NoIns/NoIns, p<0.0001; NoIns/Ins, p<0.0001) and IVS6+62A>G (G/G, p<0.0001; G/A, p<0.0001). Overall survival of ACC patients, which harboured at least one of the less frequent genotype variants of four analyzed polymorphisms (n=23), was significantly inferior (median survival: 81.0 months in patients with the common homozygous genotypes vs. 20.0 months in patients with the less frequent genotypes, HR 2.56 1.66-7.07 95% CI. P=0.001). These results were confirmed by multivariable regression analysis (HR 2.84 1.52-7.17 95% CI. P=0.037). Some TP53 polymorphisms seem to influence overall survival in ACC patients. This effect was observed for a combination of polymorphic changes rather than for single polymorphisms.European Journal of Endocrinology 02/2014; · 3.69 Impact Factor