Cancer genomics: why rare is valuable

Abstract

Rare conditions are sometimes ignored in biomedical research because of difficulties in obtaining specimens and limited interest from fund raisers. However, the study of rare diseases such as unusual cancers has again and again led to breakthroughs in our understanding of more common diseases. It is therefore unsurprising that with the development and accessibility of next-generation sequencing, much has been learnt from studying cancers that are rare and in particular those with uniform biological and clinical behavior. Herein, we describe how shotgun sequencing of cancers such as granulosa cell tumor, endometrial stromal sarcoma, epithelioid hemangioendothelioma, ameloblastoma, small-cell carcinoma of the ovary, clear-cell carcinoma of the ovary, nonepithelial ovarian tumors, chondroblastoma, and giant cell tumor of the bone has led to rapidly translatable discoveries in diagnostics and tumor taxonomies, as well as providing insights into cancer biology.

Fig. 1

A flowchart of the typical approach to a NGS study to discover novel mutations. Representative bioinformatic programs are in parenthesis and in bold (further details can be found in [–81]). For somatic mutations, tumor (T) and matched normal (N) samples, obtained from blood or adjacent normal tissue, are used in whole genome (WGSS) or exome sequencing to look for somatic mutations and copy number changes (CN). Transcriptome analysis (WTSS) of tumor samples will enable assessment of expressed mutations and fusions as well as expression patterns. Confirmation of the NGS findings using a different platform such as Sanger sequencing to eliminate false positives would be the next step. Finally, to understand the frequency of the findings in the disease of interest, analysis on a larger validation cohort of tumor samples should be completed. For hotspot mutations, sequencing; for inactivating mutations, sequencing or immunohistochemistry (IHC); and for fusions, fluorescent in situ hybridization (FISH) could be methods of choice for verification and validation

Fig. 2

Recent discoveries of mutations in forme fruste tumors revealing a broad range of pathways involved. Driver mutations from membrane receptors, to signal transducers, chromatin modifying, and remodeling complexes, as well as transcription factors and microRNA processing factors have been described in a variety of specific tumor pathologies, which may occur at low frequencies in the population. However, such insight, when followed by an understanding of the tumorigenic mechanisms involved, can vastly improve understanding of more common cancers and tumor biology in general. This figure is accompanied by Table 2 which includes a list of such tumors as well as the indicated mutations (marked by asterisks)