Risk profile of the RET A883F germline mutation: an international collaborative study

Context: The A883F germline mutation of the REarranged during Transfection proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC) the A883F mutation has been reclassified from the highest to high risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification in the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival and biochemical cure rate. Results: One and three carriers were diagnosed at age 7-9 years (median 7.5) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers had MTC diagnosed at age 10-39 years (median 19). The earliest age of MTC, regional lymph node and distant metastasis were 10, 20, 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival (both overall and disease-specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (5/8 carriers) with pertinent data. Conclusions: MTC of A883F carriers seems to have a more indolent natural course compared to that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high risk level

A Breast Cancer Risk Haplotype in the Caspase-8 Gene

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P = 8.0 × 10−5), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12–1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q = 0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer