Corey M. Gill

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

UNLABELLED Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. SIGNIFICANCE Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.

Ectopic and Serum Lipid Levels Are Positively Associated with Bone Marrow Fat in Obesity

PURPOSE To investigate the associations between ectopic and serum lipid levels and bone marrow fat, as a marker of stem cell differentiation, in young obese men and women, with the hypothesis that ectopic and serum lipid levels would be positively associated with bone marrow fat. MATERIALS AND METHODS The study was institutional review board approved and complied with HIPAA guidelines. Written informed consent was obtained. The study group comprised 106 healthy young men and women (mean age, 33.7 years ± 6.8 [standard deviation]; range, 19-45 years; mean body mass index (BMI), 33.1 kg/m(2) ± 7.1; range, 18.1-48.8 kg/m(2)) who underwent hydrogen 1((1)H) magnetic resonance (MR) spectroscopy by using a point-resolved spatially localized spectroscopy sequence at 3.0 T of L4 for bone marrow fat content, of soleus muscle for intramyocellular lipids (IMCL), and liver for intrahepatic lipids (IHL), serum cholesterol level, serum triglyceride level, and measures of insulin resistance (IR). Exercise status was assessed with the Paffenbarger activity questionnaire. RESULTS There was a positive correlation between bone marrow fat and IHL (r = 0.21, P = .048), IMCL (r = 0.27, P = .02), and serum triglyceride level (r = 0.33, P = .001), independent of BMI, age, IR, and exercise status (P < .05). High-density lipoprotein cholesterol levels were inversely associated with bone marrow fat content, independent of BMI, age, IR, and exercise status (r = -0.21, P = .019). CONCLUSION Results of this study suggest that ectopic and serum lipid levels are positively associated with bone marrow fat in obese men and women.

Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patients blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.

Positive effects of brown adipose tissue on femoral bone structure

PURPOSE Recent studies suggest a link between brown adipose tissue (BAT) and bone. The purpose of our study was to investigate the effects of BAT on femoral bone structure. MATERIALS AND METHODS We studied 105 patients (19 m, 86 f. mean age 45.5±16.1 years) who underwent F18-FDG positron emission tomography/computed tomography (PET/CT) for benign etiologies (n=20) or follow-up of successfully treated malignancies (n=85); mean time between PET/CT and last form of treatment was 14.8±18.0 months. BAT volume by PET/CT; femoral bone structure by CT (total femoral cross-sectional area (CSA), cortical CSA); and thigh muscle CSA and thigh subcutaneous fat CSA by CT was assessed. RESULTS There were positive correlations between BAT volume and total femoral CSA and cortical CSA, independent of age, BMI and history of malignancy (p<0.05). BAT volume correlated positively with thigh muscle CSA and thigh fat CSA (p<0.05). When total femoral CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables in a forward stepwise regression model, BAT volume was the only predictor of total femoral CSA. When femoral cortical CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables, BAT volume was the only predictor of femoral cortical CSA. CONCLUSION BAT volume is a positive predictor of femoral bone structure and correlates positively with thigh muscle and subcutaneous fat, possibly mediated by muscle. These results provide further evidence of a positive effect of BAT on bone.

Assessment of abdominal fat compartments using DXA in premenopausal women from anorexia nervosa to morbid obesity.

Objective: To test a newly developed dual energy X‐ray absorptiometry (DXA) method for abdominal fat depot quantification in subjects with anorexia nervosa (AN), normal weight, and obesity using CT as a gold standard.

Midtarsal break variation in modern humans: Functional causes, skeletal correlates, and paleontological implications

The midtarsal break was once treated as a dichotomous, non-overlapping trait present in the foot of non-human primates and absent in humans. Recent work indicates that there is considerable variation in human midfoot dorsiflexion, with some overlap with the ape foot. These findings have called into question the uniqueness of the human lateral midfoot, and the use of osteological features in fossil hominins to characterize the midfoot of our extinct ancestors. Here, we present data on plantar pressure and pedal mechanics in a large sample of adults and children (n = 671) to test functional hypotheses concerning variation in midfoot flexibility. Lateral midfoot peak plantar pressure correlates with both sagittal plane flexion at the lateral tarsometatarsal joint, and dorsiflexion at the hallucal metatarsophalangeal joint. The latter finding suggests that midfoot laxity may compromise hallucal propulsion. Multiple regression statistics indicate that a low arch and pronation of the foot explain 40% of variation in midfoot peak plantar pressure, independent of age and BMI. MRI scans on a small subset of study participants (n = 19) reveals that curvature of the base of the 4th metatarsal correlates with lateral midfoot plantar pressure and that specific anatomies of foot bones do indeed reflect relative midfoot flexibility. However, while the shape of the base of the 4th metatarsal may reliably reflect midfoot mobility in individual hominins, given the wide range of overlapping variation in midfoot flexibility in both apes and humans, we caution against generalizing foot function in extinct hominin species until larger fossils samples are available.

Compartmental neck fat accumulation and its relation to cardiovascular risk and metabolic syndrome

BACKGROUND Neck circumference is a predictor of cardiovascular disease (CVD) risk. However, detailed assessment of neck fat has not been explored, and the contribution from individual neck fat compartments to CVD risk is unknown. OBJECTIVE The objective was to measure neck adipose tissue (NAT) compartments and examine relations with CVD risk markers, with the hypothesis that neck adipose tissue (NAT) accumulation preferentially involves specific compartments that contribute differently to metabolic risk. DESIGN We retrospectively studied 303 subjects with successfully treated malignancies or benign etiologies [151 women, 152 men; mean (± SD) age: 55 ± 17 y; mean body mass index (BMI; in kg/m(2)): 28 ± 6] who underwent whole-body positron emission tomography/computed tomography. NAT was measured at the level of the C5 vertebral body, subdivided into posterior (NATpost), subcutaneous (NATsc), and perivertebral (NATperivert) compartments. Data on CVD risk factors (BMI, abdominal circumference, visceral and abdominal subcutaneous adipose tissue, blood pressure, serum lipids, and fasting plasma glucose) were collected. We compared NAT compartments across lean, overweight, and obese groups and performed multivariate regression models correlating NAT with CVD risk factors. Receiver operating characteristic curve and prevalence ratio analyses were performed to examine the association of NAT compartments with metabolic syndrome. RESULTS NATpost and NATsc were more consistently associated with cardiometabolic risk, especially in women, correlating with visceral adipose tissue (P < 0.0001) and triglycerides (P < 0.001) and a nearly 1.5-fold increase in the prevalence ratio for metabolic syndrome after adjustment for age and BMI (P < 0.05). NATsc was most abundant in women, whereas intermuscular compartments (NATpost and NATperivert) were higher in men. In both sexes, NATpost and NATperivert showed the largest increment between lean and obese subjects. CONCLUSIONS Neck fat compartments expand differently with increasing adiposity, correlate with CVD risk factors, and are associated with metabolic syndrome, most notably NATpost and NATsc in women. Although neck circumference remains an important method to assess metabolic risk, cross-sectional NAT assessment provides further insight into fat accumulation in the neck. This trial was registered at clinicaltrials.gov as NCT02205021.

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.

Background Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. Methods To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. Results The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. Conclusion We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas

OBJECTIVE Meningiomas located in the skull base are surgically challenging. Recent genomic research has identified oncogenic SMO and AKT1 mutations in a small subset of meningiomas. METHODS The authors performed targeted sequencing in a large cohort of patients with anterior skull base meningiomas (n = 62) to better define the frequency of SMO and AKT1 mutations in these tumors. RESULTS The authors found SMO mutations in 7 of 62 (11%) and AKT1 mutations in 12 of 62 (19%) of their cohort. Of the 7 meningiomas with SMO mutations, 6 (86%) occurred in the olfactory groove. Meningiomas with an SMO mutation presented with significantly larger tumor volume (70.6 ± 36.3 cm3) compared with AKT1-mutated (18.2 ± 26.8 cm3) and wild-type (22.7 ± 23.9 cm3) meningiomas, respectively. CONCLUSIONS Combined, these data demonstrate clinically actionable mutations in 30% of anterior skull base meningiomas and suggest an association between SMO mutation status and tumor volume. Genotyping of SMO and AKT1 is likely to be high yield in anterior skull base meningiomas with available surgical tissue.

Treatment of brain metastases in the modern genomic era

ABSTRACT Development of brain metastasis (BM) portends a dismal prognosis for patients with cancer. Melanomas and carcinomas of the lung, breast, and kidney are the most common malignancies to metastasize to the brain. Recent advances in molecular genetics have enabled the identification of actionable, clinically relevant genetic alterations within primary tumors and their corresponding metastases. Adoption of genotype‐guided treatment strategies for the management of systemic malignancy has resulted in dramatic and durable responses. Unfortunately, despite these therapeutic advances, central nervous system (CNS) relapses are not uncommon. Although these relapses have historically been attributed to limited blood brain barrier penetration of anti‐neoplastic agents, recent work has demonstrated genetic heterogeneity such that metastatic sites, including BM, harbor relevant genetic alterations that are not present in primary tumor biopsies. This improved insight into molecular mechanisms underlying site specific recurrences can inform strategies for targeting these oncogenic drivers. Thus, development of rational, genomically guided CNS‐penetrant therapies is crucial for ongoing therapeutic success.