A Comprehensive Assessment of Somatic Mutation Calling in Cancer Genomes
Authors: Alioto Tyler S. , Derdak Sophia , Beck Timothy A. , Boutros Paul C. , Bower Lawrence , Buchhalter Ivo , Eldridge Matthew D. , Harding Nicholas J , Heisler Lawrence E. , Hovig Eivind , Jones David T. W. , Lynch Andrew G. , Nakken Sigve , Ribeca Paolo , Sertier Anne-Sophie , Simpson Jared T. , Spellman Paul , Tarpey Patrick , Tonon Laurie , Vodák Daniel , Yamaguchi Takafumi N. , Agullo Sergi Beltran , Dabad Marc , Denroche Robert E. , Ginsbach Philip , Heath Simon C. , Raineri Emanuele , Anderson Charlotte L. , Brors Benedikt , Drews Ruben , Eils Roland , Fujimoto Akihiro , Giner Francesc Castro , He Minghui , Hennings-Yeomans Pablo , Hutter Barbara , Jäger Natalie , Kabbe Rolf , Kandoth Cyriac , Lee Semin , Létourneau Louis , Ma Singer , Nakagawa Hidewaki , Paramasivam Nagarajan , Patch Anne-Marie , Peto Myron , Schlesner Matthias , Seth Sahil , Torrents David , Wheeler David A. , Xi Liu , Zhang John , Gerhard Daniela S. , Quesada Víctor , Valdés-Mas Rafael , Gut Marta , Hudson Thomas J. , McPherson John D. , Puente Xose S. , Gut Ivo G. 
Published: December 2014

The emergence of next generation DNA sequencing technology is enabling high-resolution cancer genome analysis. Large-scale projects like the International Cancer Genome Consortium (ICGC) are systematically scanning cancer genomes to identify recurrent somatic mutations. Second generation DNA sequencing, however, is still an evolving technology and procedures, both experimental and analytical, are constantly changing. Thus the research community is still defining a set of best practices for cancer genome data analysis, with no single protocol emerging to fulfil this role. Here we describe an extensive benchmark exercise to identify and resolve issues of somatic mutation calling. Whole genome sequence datasets comprising tumor-normal pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, were shared within the ICGC and submissions of somatic mutation calls were compared to verified mutations and to each other. Varying strategies to call mutations, incomplete awareness of sources of artefacts, and even lack of agreement on what constitutes an artefact or real mutation manifested in widely varying mutation call rates and somewhat low concordance among submissions. We conclude that somatic mutation calling remains an unsolved problem. However, we have identified many issues that are easy to remedy that are presented here. Our study highlights critical issues that need to be addressed before this valuable technology can be routinely used to inform clinical decision-making.

Abbreviations and Definitions

SSM

Somatic Single-base Mutations or Simple Somatic Mutations, refers to a somatic single base change

SIM

Somatic Insertion/deletion Mutation

CNV

Copy Number Variant

SV

Structural Variant

SNP

Single Nucleotide Polymorphisms, refers to a single base variable position in the germline with a frequency of > 1% in the general population

CLL

Chronic Lymphocytic Leukaemia

MB

Medulloblastoma

ICGC

International Cancer Genome Consortium

BM

Benchmark

aligner = mapper, these terms are used interchangeably