Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.

GENETIC SYNDROMES PREDISPOSING TO PEDIATRIC BRAIN TUMORS

The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8–19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (NF1, P53). In addition, large scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes (ELP1 alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common tumor predisposition syndromes. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features and treatment implications.

Genetic alteration of ARMC5 in a patient diagnosed with meningioma and primary macronodular adrenal hyperplasia: a case report

A monoallelic germline alteration of ARMC5 causes primary bilateral macronodular adrenal hyperplasia (PBMAH) with Cushing’s syndrome via its subsequent somatic alteration on the other allele as the second hit. PBMAH is sometimes complicated with meningioma. Dependency of such a multi-organ disease on the second hit mechanism was reported before, but this finding has not been confirmed yet. We describe a case of a 65-year-old female with PBMAH, carrying a heterozygous germline alteration of ARMC5, p.R267*, complicated with meningioma associated with somatic loss of heterozygosity (LOH) of the unaffected allele. Pathogenic alterations of ARMC5 may also contribute to the development of meningioma by the two-hit mechanism.

Growth Rates of Genetically Defined Renal Tumors: Implications for Active Surveillance and Intervention

PURPOSE Published series of growth rates of renal tumors on active surveillance largely consist of tumors without pathologic or genetic data. Growth kinetics of genetically defined renal tumors are not well known. Here, we evaluate the growth of genetically defined renal tumors and their association with patient clinical and genetic characteristics. PATIENTS AND METHODS We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of VHL, MET, FLCN, or BAP1 with at least 1 solid renal mass managed with active surveillance at our institution. Tumor growth rates (GR) were calculated and patients were stratified by genetic alteration and other clinical and genetic factors to analyze differences in growth rates using linear regression and comparative statistics. RESULTS A total of 292 patients with 435 genetically defined tumors were identified, including 286 VHL-deficient, 91 FLCN-deficient, 52 MET-activated, and 6 BAP1-deficient tumors. There were significant differences in GRs when stratified by genetic alteration. BAP1-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range [IQR], 0.57-0.68 cm/y), followed by VHL-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y), FLCN-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with MET activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y; P < .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR ( P = .005). CONCLUSION In a cohort of genetically defined tumors, tumor growth rates varied in a clinically and statistically different manner according to genetic subtype. Rapid growth of BAP1-deficient tumors indicates that these patients should be managed with caution. The faster growth of tumors in younger patients may support more frequent imaging, whereas the slower growth of other tumors may support extended surveillance beyond annual imaging in some instances.

First-line sunitinib in patients with renal cell carcinoma (RCC) and von Hippel-Lindau syndrome (VHL).

373 Background: VHL is a rare hereditary condition caused by germline alteration of VHL gene predisposing to multiple renal and other tumors. Since acquired dysregulation of VHL-dependent pathways is often present in patients with sporadic RCC treated with first-line sunitinib (SUN), there is a strong rationale to use the same drug in VHL patients with progressive disease in the kidneys or other sites. Methods: We performed a retrospective analysis of SUN therapy in genetically confirmed VHL patients treated at our Institution for multifocal or advanced RCC. Results: From February 2007 to October 2010, 9 VHL patients were proposed first-line SUN for RCC, mean age 44 yrs (26-60), F:M ratio 2:1. SUN was administered for a mean of 9 cycles (1-20). Eight of 9 pts received at least two cycles and were considered for response evaluation: all 8 were stable according to RECIST criteria, but decrease in radiological density of lesions was observed in 7 of 8 pts (87.5%). Density decrease was noted not only in renal and hepatic lesions but also in some pancreatic nodules; all CNS haemangioblastoma lesions remained stable (see table). Preliminary median PFS is > 13 months (8 censored, 1 deceased). Conclusions: SUN treatment in VHL patients appears to achieve good disease control not only in renal tumors but also in synchronous VHL-related lesions, especially pancreatic solid nodules whose exact nature (metastatic RCC or neuroendocrine tumor) cannot be ruled out without invasive biopsies. [Table: see text] No significant financial relationships to disclose.