Publications

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP). However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

BACKGROUND

Mapping and ablation of fractionated electrograms is a common treatment for scar-based ventricular tachycardia (VT). An automated algorithm has been developed for rapid "fractionation mapping."

METHODS

Electroanatomic maps from 21 ablation procedures (14 scar-based VT and seven control idiopathic VT/premature ventricular contractions with normal voltage) were retrospectively analyzed using the Ensite Precision fractionation map (fMap; Abbott Laboratories; Abbott Park, IL, USA) algorithm. For each study, voltage maps and 30 fMaps were generated using combinations of parameters: width (5, 10, 20 ms), refractory time (15, 30 ms), sensitivity (0.1, 0.2 mV), and fractionation threshold (2, 3, 5). Parameter sensitivity was assessed by overlap of fractionated areas (fArea) with successful VT ablation sites (defined by entrainment and/or pace mapping). Specificity was assessed by presence of fractionated areas in control patients.

RESULTS

Of the 30 fMap parameter sets tested, seven identified >50% of scar-based VT ablation sites, and 26 contained <5 cm fractionation on control fMaps. Three combinations of fMap width/refractory/sensitivity/threshold parameters met both of the above criteria, and 20/30/0.1/2 identified the most VT ablation sites (79%) and generated 42.3 ± 28.2 cm of fArea on scar-based VT maps compared with 4.9 ± 3.2 cm on control maps (P = .001). None of the control patients and 23% of the scar-based VT patients had VT recurrence at mean 15 month follow-up.

CONCLUSION

Careful selection of signal processing parameters optimizes sensitivity and specificity of automated fractionation mapping for scar-based VT. Real-time use of fMap algorithms may reduce VT ablation procedure time and improve substrate modification, which may improve outcomes.