Year: 2017
Type: article
Study design: Observational Study
Abstract: Metastasis is the most common source of tumors in the brain. Despite their prominence, the biology of brain metastases remains poorly understood making prognosis poor and the need for additional treatment options is urgent. We performed targeted genetic profiling of primary tumors and metastases (brain and systemic) to elucidate brain-associated alterations and prioritize potential targets for brain metastasis treatment. Tumor profiling involved multiplatform analyses including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (immunohistochemistry) and gene amplification of 16,999 unmatched primary/metastasis samples: 8178 non-small cell lung cancers (5098 primaries; 2787 systemic metastases; 293 brain metastases), 7064 breast cancers (3496 primaries; 3469 systemic metastases; 99 brain metastases), and 1757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). Across pathologies, TOP2A, which controls and alters the topologic states of DNA during transcription, was the most frequently expressed protein in brain metastasis relative to the primary (NSCLC: 74.5% versus 55%, P <0.0001; breast cancer: 78.8% versus 50.1%, P = 0.0001; melanoma: 76.4% versus 45.8%, P=0.0011). Two additional enzymes involved in DNA synthesis and chemoresistance, RRM1, and TS, were also increased in NSCLC brain metastases relative to the primary (31.8% versus 20.9%, P = 0.0049; and 34.9% versus 21.5%, P = 0.0006, respectively). Other DNA topoisomerases and enzymes essential for DNA replication/repair such as TOPO1 (77.9% versus 63.4%, P = 0.0357) and ERCC1 (61.8% versus 42.1%, P= 0.0199) were also more frequently expressed in breast cancer brain metastases. Unique to melanoma brain metastases was increased cMET expression frequency relative to the primary (36.4% versus 7.9%, P=0.0003). We report enriched expression of markers associated with DNA synthesis, replication, and repair in brain metastases compared with primary cancer specimens. This trend occurred across all tumor histologies, supporting the prioritization of therapies that target these pathways.
Source: Neuro-Oncology
Authors: Sherise Ferguson, Siyuan Zheng, Joanne Xiu, Shouhao Zhou, Mustafa Khasraw, Priscilla K Brastianos, Santosh Kesari, Jethro Hu, Jeremy Rudnick, Michael Salacz, David Piccioni, Huang Suyun, Micheal Davies, Isabella Glitza, John Heymach, Jianjun Zhang, Nuhad Ibrahim, John de Groot, Joseph McCarty, Barbara J O’Brien, Raymond Sawaya, Roel Verhaak, Sandeep Reddy, Waldemar Priebe, David Spetzler, Amy Heimberger
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767644850