Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data

Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals. A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients. We present here FounderTracker, a computational method for the genome-wide detection of founder mutations in cancer using dense tumor SNP profiles. Our method is based on two assumptions. First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers. Second, the overlap between the ancestral chromosome fragments inherited from a common founder will define a minimal haplotype conserved in each patient carrying the founder mutation. Our approach thus relies on the detection of haplotypes with significant identity by descent (IBD) sharing within recurrent regions of LOH to highlight genomic loci likely to harbor a founder mutation. We validated this approach by analyzing two real cancer data sets in which we successfully identified founder mutations of well-characterized tumor suppressor genes. We then used simulated data to evaluate the ability of our method to detect IBD tracts as a function of their size and frequency. We show that FounderTracker can detect haplotypes of low prevalence with high power and specificity, significantly outperforming existing methods. FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the “missing” heritability in cancer. This method is freely available and can be used online at the FounderTracker website

Clinical and outcome characteristics of children with adrenocortical tumors: A report from the international pediatric adrenocortical tumor registry

Purpose We created a registry for pediatric adrenocortical tumors (ACTS), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. Patients and Methods Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. Results The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% Cl, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. Conclusion Childhood ACTS occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information. (C) 2004 by American Society of Clinical Oncology.22583884

Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma - Mitotane monitoring and tumor regression

Purpose: To define a mitotane dose for pediatric patients with adrenocortical cancer (ACC) that maintains therapeutic plasma levels (TL) between 14 and 20 mu g/mL and to verify its antitumor efficacy in association with 8 cycles of cisplatin, etoposide, and doxorubicin (CED). Methods: Powdered mitotane was dissolved in a medium chain triglyceride oil and administered to 11 children with ACC (2.4 to 15.4 y of age); an initial low dose was increased to 4 g/m(2)/d. Ten of the 11 children had a germline TP53 R337H mutation. Mitotane plasma levels were determined using high-performance liquid chromatography. Results: The mitotane dose to maintain TL in 7 patients ranged from 1.0 to 5.3 g/m(2)/d. Six children reached mitotane levels of 10 mu g/mL in 3.6 months (1.5 to 5.0mo), whereas 5 children took 8 months (6.5 to 12.5 mo). Minor to partial tumor remission was found in 5 patients (< 1 y) and complete remission was found in 2 patients. Of the 3 patients who are alive at the time of report, 1 patient has been without disease for 16 months, and 2 patients have progressive disease. All patients had recurrent metastatic disease (2 to 9 times). Mitotane toxic effects were nausea, diarrhea, vomiting, neurologic alterations, gynecomastia, a rare case of hypertensive encephalopathy, and CED-related hematologic toxic effects. Conclusions: Mitotane daily dose to maintain TL is variable and monitoring should start 1.5 months after the beginning of treatment. CED combined with mitotane is the best available pharmacologic treatment for ACC, but further studies are required to characterize different profiles of therapeutic response.28851352