TOP 8 in Cancer Genomics, 2016

By Julija Hmeljak

I’m not going to lie; I am no computational biologist. Even though anything “omics” has been all the rage in cancer research for the past decade, I used to sit firmly on the “Genomics Papers Are Boring” train. But the day came when, out of necessity, I started reading papers on genomics, and the subject itself blew my little mind. Since cancer research occupies approximately 45 % of my time, cancer genomics papers are the ones I have the strongest feelings about. And where do these feelings come from? Mostly they stem from my postdoctoral project, which focuses on characterizing the biological consequences of specific mutations in cancer.

Image Credit: Holly Gramazio (Attribution-NonCommercial 2.0 Generic (CC BY-NC 2.0) lincese to reproduce the image)

Yet, reading scientific papers is just as much part of research as conducting experiments. Sometimes, reading scientific papers to answer questions for my own research leads me to recreational reading outside my specific field. That’s exactly what this roundup is meant to be – a roster of cancer genomics papers that might be outside your reading list, but are so good that you shouldn’t miss them. I evaluated each paper’s scientific merit, study design, and presentation style to compile my top 8 cancer genomics papers of 2016, ranked as follows:

8. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Bueno et al., Nat Gen (2016); 48: 407-416. DOI: 10.1038/ng.3520 

The first entry in my list is a “classic” descriptive genomics paper. Despite seemingly lacking some of the panache that other papers on this list have, this paper is a Big Deal for mesothelioma researchers, as it provides the largest molecular profiling study for this difficult organ-lining cancer type. Their correlations of molecular signatures with tumor subtypes are especially fascinating, as they provide some necessary understanding of molecular processes that drive phenotypes with a high impact on disease prognosis.

7. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer

Kumar, Coleman et al., Nat Med (2016); 22: 369-378; DOI: 10.1038/nm.4053 

This paper elegantly tackles one of the scourges of oncology: tumor heterogeneity and its most impactful consequence—recurrence after therapeutic intervention. To identify if molecular drivers are shared among individual tumor nodules within the same individual, the authors sequenced multiple prostate tumors and compared mutational, transcriptional, and copy number landscapes within and between individual patients. The paper’s main conclusion was that major genetic drivers identified in a single metastasis can provide a reasonably good basis for extrapolation to other tumors within an individual prostate cancer patient.

6. Mutational signatures associated with tobacco smoking in human cancer

Alexandrov et al., Science (2016); 354: 618-622; DOI: 10.1126/science.aag0299 

A massive one – the sheer size of the endeavor would warrant this paper a spot on the list, but the authors managed to take it further. They analyzed more than 5000 samples of cancer types typically linked with tobacco smoking. Comparing cases by smoking status allowed the authors to identify the effects of tobacco smoke on DNA sequence and methylation pattern alterations, and, importantly, evaluate the contributions of different mutational signatures to the genomic landscape in smokers and non-smokers. Interestingly, they found that tobacco smoke affects DNA sequence much more significantly than it affects methylation patterns.   

5. Mutational signatures of ionizing radiation in second malignancies

Behjati, Gundem et al., Nat Comm (2016); 7: 12605; DOI: 10.1038/ncomms12605

Radiation is one of the most frequently used therapeutic approaches for cancer patients. Secondary cancers due to ionizing radiation are a well-recognized risk, although radiation’s exact effects on DNA had not previously been mapped. This paper investigates the mutational processes that occur in secondary, radiation-induced cancers and identifies two distinct mutational signatures of ionizing radiation. These signatures might help explain the mutagenic and carcinogenic potential of ionizing radiation, either in causing primary or secondary cancers.

4. Functional genomics landscape of human breast cancers drivers, vulnerabilities and resistance

Marcotte et al., Cell (2016); 164: 293-309; DOI: 10.1016/j.cell.2015.11.062

A smooth integration of dropout RNAi screens, which are designed to identify genes whose expression is of fundamental importance for survival of a cell line, on a whopping 77 breast cancer cell lines and large-scale genomics to identify both general and context-dependent genes essential to breast cancer progression, drug sensitivities, and resistance mechanisms. The strongest value of this paper is in its using a large panel of cell lines to minimize potential bias that can arise from using heterogeneous cell lines.

3The genomic landscape of male breast cancers

Piscuoglio et al., Clin Cancer Res (2016); 22: 4045-56; DOI: 10.1158/1078-0532.CCR-15-2840 

Second breast cancer entry on the list. This time, the work was done in humans. Male humans. Breast cancer’s devastating frequency in female patients is common knowledge, but males are at risk, too. Due to its rarity, comprehensive studies are difficult to carry out, and the paucity of studies affects treatment strategies, which are usually extrapolated from results of studies on female patients. This comparative study of male versus female luminal breast cancer relied on a targeted sequencing panel that identified a distinct repertoire of genomic alterations specific to male breast tumors.

2. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

Notta et al., Nature (2016); 538: 378-382; DOI: 10.1038/nature19823 

Pancreatic adenocarcinoma is a uniformly fatal cancer that was classically regarded to have a step-wise development trajectory demarcated by distinct acquired DNA sequence alterations, which result in a progressively more malignant disease. This paper challenges this classic linear model and provides insight into the divergent evolution of both the precursor and tumor lesion lineages.

1. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants

Sulak et al., eLIFE (2016): 5:e11994; DOI: 10.7554/eLife.11994 

A cheeky one, but irresistible. Spoiler: ELEPHANTS! In all seriousness, this very interesting and, may I say endearing, study analyzed the mechanisms of “Peto’s Paradox” – the lack of apparent correlation between body size and cancer risk. The authors confirmed that “Peto’s Paradox” is grounded in genomic amplifications of the TP53 locus and the evolutionary co-occurrence of this amplification with increasing body size in the Proboscidean lineage.  

Disclaimer: this list is subjective. There have been numerous remarkable achievements in cancer genomics this year, and there are many more exciting papers within our reach. The subject of cancer genomics is constantly evolving, with fascinating advances made every day. Here’s to reading about those advances in 2017 and onwards!

Julija Hmeljak is a postdoctoral fellow at Memorial Sloan Kettering Cancer Center in New York City.

Editors: Tristan Fehr and Yue Liu