High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

Abstract

Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here, we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas identified some differences and suggested an enrichment of treatment-refractory samples in breast and lung cancer cohorts. To illustrate novelty within the dataset, we surveyed the genomic landscape of rare diseases and identified an increased frequency of NOTCH1 alterations in adenoid cystic carcinomas compared with previous studies. Analysis of tumor suppressor gene patterns revealed disease specificity for certain genes but broad inactivation of others. We identified multiple potentially druggable, novel and known kinase fusions in diseases beyond those in which they are currently recognized. Analysis of variants of unknown significance identified an enrichment of SMAD4 alterations in colon cancer and other rare alterations predicted to have functional impact. Analysis of established, clinically relevant alterations highlighted the spectrum of molecular changes for which testing is currently recommended, as well as opportunities for expansion of indications for use of approved targeted therapies. Overall, this dataset presents a new resource with which to investigate rare alterations and diseases, validate clinical relevance, and identify novel therapeutic targets. Cancer Res; 77(9); 2464–75. ©2017 AACR.

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…2016), and, more commonly, in radiation-associated PTC (about 60%) (Ricarte-Filho et al 2013) and in pediatric, adolescent and young adult PTC (27%) (Vanden Borre et al 2017). Similar fusions have been identified in other cancers, including lung adenocarcinoma (ADC) (1–2%, Chen et al 2014), colorectal carcinoma (0.2%, Le Rolle et al 2015), Spitzoid neoplasms (3%, Wiesner et al 2014), salivary gland carcinoma (1.9% adenocarcinoma and 4.9% ductal carcinoma, Wang et al 2016) and in single cases of chronic myelomonocitic leukemia (CMML) (Ballerini et al 2012), primary myelofibrosis (Bossi et al 2014), gastrointestinal neuroendocrine tumor (Hartmaier et al. 2017), and breast invasive carcinoma (Stransky et al 2014).…”

Spindle cell tumour with S100 and CD34 co‐expression showing PDZRN3–RAF1 rearrangement – a recently described entity

“…The case in this study represents the second case of this entity with a characterised PDZRN3–RAF1 gene fusion. Of note, PDZRN3–RAF1 gene fusions have also been reported in pancreatic adenocarcinomas over a range of breakpoint regions . MTAP on chromosome 9 is another RAF1 fusion partner that has been recently described in an S100 positive soft tissue sarcoma .…”

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

“…AF represents the percentage of mutant DNA allele reads relative to total DNA allele reads (mutant plus wild type). Custom filtering was applied to report GAs and remove benign germline events as described previously (13). Maximum somatic allele frequency (MSAF) measures the AF of all somatic alterations (including reportable GAs, variants of unknown significance, and synonymous mutations) identified per sample; alterations in the ExAC database are removed from the alteration list for MSAF calculation as they are likely germline, and dbSNP variants are also excluded.…”

“…Twenty-five patients in this series had a paired tissue sample that was sequenced using hybrid capture-based genomic profiling (FoundationOne) according to previously published methods (13, 14). For comparative analyses with prior studies, data from the FoundationCORE database (tissue samples analyzed using the FoundationOne assay), TCGA (15), and the Giannakis and colleagues’ study (16) were extracted from cBioPortal (17) in July 2017.…”