Faculty Bibliography

Focal cortical dysplasia (FCD) is a malformation of cortical development that is associated with high rates of cognitive morbidity. However, the degree to which specific irregularities of dysplastic tissue directly impact cognition remains unknown. This study investigates the relationship between blurring of the cortical gray and white matter boundary on magnetic resonance imaging (MRI) and global cognitive abilities in FCD. Gray-white blurring (GWB) is quantified by sampling the non-normalized T1 image intensity contrast above and below the gray and white matter interface along the cortical mantle. Spherical averaging is used to compare resulting GWB for patients with histopathologically verified FCD with matched controls. Whole-brain correlational analyses are used to investigate the relationship between blurring and general cognitive abilities, controlling for epilepsy duration. Results show that cognitive performance is reduced in patients with FCD relative to controls. Patients show increased GWB in bilateral temporal, parietal, and frontal regions. Furthermore, increased GWB in these regions is linearly related to decreased cognition and mediates group differences in cognitive performance. These findings demonstrate that GWB is a marker of reduced cognitive efficiency in FCD that can potentially be used to probe general and domain-specific cognitive functions in other neurological disorders.

It is currently unclear whether Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. We found that derepressed CRL4(DCAF1) promotes YAP- and TEAD-dependent transcription by ubiquitylating and, thereby, inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2-mutant tumors. We conclude that derepressed CRL4(DCAF1) promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients' path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.