Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer

INTRODUCTION: Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. We hypothesized that germline mutations in FANCD2, BRIP1/BACH1, LMO4 and SFN may account for some of the unexplained multiple-case breast cancer families. METHODS: The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I). RESULTS: DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity. CONCLUSION: There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk

High-temperature irradiation test of UO₂ cermet fuels /

Niobium-clad niobium cermets and Type 430 stainless steel-clad molybdenum and chromium cermets, all containing 80 vol% 20% enriched UO₂, prepared by vapordeposition techniques or from the powders and densified and clad by gas-pressure bonding, were subjected to hightemperature high-heat-flux irradiation in the MTR. Two instrumerted double-walled capsules, each containing duplicate NaK-immersed cylindrical specimens of the three compositions were involved. Specimen diameters were varied according to the particular cermet thermal conductivity in an attempt to secure central temperatures of about 0.6 of the matrix melting point. Probably because of weld failures in both capsules, irradiation temperatures were higher than intended, causing loss of the chromium cermets in one capsule and all of the cermets in the other capsule. The remaining specimens were given a postirradiation dimensional and metallographic examination. The niobium-clad niobium-UO₂ cermet exhibited excellent stability at estimated center-line temperatures above 2500 deg F. A density decrease of only 1.4% was measured at a burnup of about 4 at.%. Although the capsule overheating caused the molybdenum-UO₂ cermet to partially melt, areas only a few mils from the melted zone showed no evidence of damage from the adverse conditions of the irradiation. (auth)."January 7, 1963."Includes bibliographical references (p. 20)Niobium-clad niobium cermets and Type 430 stainless steel-clad molybdenum and chromium cermets, all containing 80 vol% 20% enriched UO₂, prepared by vapordeposition techniques or from the powders and densified and clad by gas-pressure bonding, were subjected to hightemperature high-heat-flux irradiation in the MTR. Two instrumerted double-walled capsules, each containing duplicate NaK-immersed cylindrical specimens of the three compositions were involved. Specimen diameters were varied according to the particular cermet thermal conductivity in an attempt to secure central temperatures of about 0.6 of the matrix melting point. Probably because of weld failures in both capsules, irradiation temperatures were higher than intended, causing loss of the chromium cermets in one capsule and all of the cermets in the other capsule. The remaining specimens were given a postirradiation dimensional and metallographic examination. The niobium-clad niobium-UO₂ cermet exhibited excellent stability at estimated center-line temperatures above 2500 deg F. A density decrease of only 1.4% was measured at a burnup of about 4 at.%. Although the capsule overheating caused the molybdenum-UO₂ cermet to partially melt, areas only a few mils from the melted zone showed no evidence of damage from the adverse conditions of the irradiation. (auth).Work performed by the Battelle Memorial InstituteMode of access: Internet