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In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types. [ABSTRACT FROM AUTHOR]

We describe the design and performance of BRPET, a novel dedicated breast PET (dbPET) scanner designed to maximize visualization of posterior regions of the breast. BRPET uses prone imaging geometry and a 12-module detector ring built from pixelated LYSO crystals coupled to position sensitive photomultiplier tubes (PSPMTs). Optical coupling via slanted plastic fiber optic light guides permits partial insertion of the crystals into the exam table's breast aperture. Image quality testing procedures were adapted from the NEMA NU4-2008 protocol. Two additional phantom tests quantified the posterior extent of the usable volume of view (VoV). BRPET axial, radial, and tangential FWHM spatial resolutions at the isocenter were 1.8,1.7, and 1.9 mm, respectively. The peak absolute system sensitivity was 0.97% using an energy window of 460-562 keV. The peak noise equivalent counting rate was 5.33 kcps at 21.6 MBq. The scanner VoV extends to within ~6 mm of the plane defining the location of the chest wall. A pilot human study (n = 10) compared the diagnostic performance of FDG-BRPET to that of contrast enhanced MRI (CEMRI), with biopsy as ground truth. Averaged over three expert human observers, the sensitivity/specificity for BRPET was 0.93/1.0, compared to 1.0/0.25 for CEMRI. [ABSTRACT FROM AUTHOR]