BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma

Purpose From epidemiological studies it appears that breast cancer (BC) and cutaneous melanoma (CMM) in the same individual occur at a higher frequency than expected by chance. Genetic factors common to both cancers can be suspected. Our goal was to estimate the involvement of "high risk" genes in patients presenting these two neoplasia, selected irrespectively from family history and age at diagnosis. Experimental Design Eighty two patients with BC and CMM were screened for BRCA1, BRCA2, TP53, CDKN2A and CDK4 (exon 2) germline mutations. Results Deleterious mutations were identified in 6 patients: two carriers of a BRCA1 germline mutation, two carriers of TP53 germline mutations (one of which also harbored a BRCA2 deleterious mutation, the other one a BRCA2 unclassified variant), and two carriers of a CDKN2A germline mutation. In addition, 6 variants of unknown signification were identified in BRCA1 or BRCA2 genes. Regarding family history, 3/13 (23%) patients with a positive family history of BC or CMM were carriers of a germline mutation, whereas only 3/69 (4%) patients without family history were carriers of a germline mutation. Conclusion Our findings show that few patients with BC and CMM who lacked family histories of these cancers are carriers of deleterious germline mutations in four of the five genes we examined. We describe for the first time, two simultaneous BRCA2 and TP53 mutations, suggesting that analysis in more than one gene could be performed if a patient's personal or familial history does not match a single syndrome

Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis

RATIONALE: Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. OBJECTIVE: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. METHODS: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (N=3,624) and controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test. MEASUREMENTS AND MAIN RESULTS: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant, rs35705950, with an OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in risk of IPF in the TERT and RTEL1 gene regions, and found that the FAM13A and TERT regions have independent common and rare variant signals. CONCLUSIONS: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions; these genetic variants focus on biological mechanisms of host defense and cell senescence