A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.

Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.

Baseline Mammography: What Is It and Why Is It Important? A Cross-Sectional Survey of Women Undergoing Screening Mammography.

OBJECTIVES: Studies have shown that having a baseline mammogram, the first screening mammogram, available for comparison at the time of interpreting a subsequent mammogram significantly decreases the potential of a false-positive examination. Our aim was to evaluate knowledge of and perception about the significance of baseline mammograms in those women undergoing screening mammography. MATERIALS AND METHODS: A cross-sectional prospective survey study was conducted in women without a history of breast cancer presenting for their screening mammogram. Respondents were surveyed anonymously between March and April 2017. The questionnaire was developed by primary care providers and radiologists and pretested for readability and clarity. RESULTS: In all, 401 women (87% white, 93% educated beyond high school) completed surveys in which 77% of women reported having yearly mammograms, 31% reported having a history of an abnormal mammogram, and 45% had not heard the term baseline mammogram. Of those who had heard the term, the most commonly reported source was their primary care provider (31%). Although 74% chose the correct definition of a baseline mammogram, 67% did not think that a baseline mammogram was important for decreasing associated cost, time, and discomfort due to the number of mammograms incorrectly read as abnormal. CONCLUSION: In a group of educated women who routinely get mammograms, almost one-half had not heard the term baseline mammogram. Furthermore, most women did not think baseline mammography was important for decreasing associated cost, time, and discomfort due to mammograms incorrectly read as abnormal. This study suggests that efforts to improve women's understanding of baseline mammograms and their importance are warranted, with greatest opportunity for health care providers and radiologists.

Fractal topology of gene promoter networks at phase transitions.

Much is known regarding the structure and logic of genetic regulatory networks. Less understood is the contextual organization of promoter signals used during transcription initiation, the most pivotal stage during gene expression. Here we show that promoter networks organize spontaneously at a dimension between the 1-dimension of the DNA and 3-dimension of the cell. Network methods were used to visualize the global structure of E. coli sigma (sigma) recognition footprints using published promoter sequences (RegulonDB). Footprints were rendered as networks with weighted edges representing bp-sharing between promoters (nodes). Serial thresholding revealed phase transitions at positions predicted by percolation theory, and nuclei denoting short steps through promoter space with geometrically constrained linkages. The network nuclei are fractals, a power-law organization not yet described for promoters. Genome-wide promoter abundance also scaled as a power-law. We propose a general model for the development of a fractal nucleus in a transcriptional grammar.