High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer

Abstract

BackgroundColorectal cancer with metastases limited to the liver (liver-limited mCRC) is a distinct clinical subset characterized by possible cure with surgery. We performed high-depth sequencing of over 750 cancer-associated genes and copy number profiling in matched primary, metastasis and normal tissues to characterize genomic progression in 18 patients with liver-limited mCRC.ResultsHigh depth Illumina sequencing and use of three different variant callers enable comprehensive and accurate identification of somatic variants down to 2.5% variant allele frequency. We identify a median of 11 somatic single nucleotide variants (SNVs) per tumor. Across patients, a median of 79.3% of somatic SNVs present in the primary are present in the metastasis and 81.7% of all alterations present in the metastasis are present in the primary. Private alterations are found at lower allele frequencies; a different mutational signature characterized shared and private variants, suggesting distinct mutational processes. Using B-allele frequencies of heterozygous germline SNPs and copy number profiling, we find that broad regions of allelic imbalance and focal copy number changes, respectively, are generally shared between the primary tumor and metastasis.ConclusionsOur analyses point to high genomic concordance of primary tumor and metastasis, with a thick common trunk and smaller genomic branches in general support of the linear progression model in most patients with liver-limited mCRC. More extensive studies are warranted to further characterize genomic progression in this important clinical population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0589-1) contains supplementary material, which is available to authorized users.

Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer

“…Indeed, this was the case in both CRC patients in which the driver mutations (APC, KRAS, TP53, NRAS, CDK4) were found in both the primary and metastatic organ sites. These data are also consistent with previous NGS data that have reported a high concordance of primary and metastatic tumor mutations (Brannon et al 2014;Tan et al 2015).…”

“…Further work has begun to investigate the mutational concordance of matched primary and metastatic tumors in CRC patients by next-generation sequencing. In a study that profiled microsatellite-stable (MSS) CRC patients, a large number of mutations were reported as being concordant between the primary and metastatic tumors, in addition to a small number of metastasis-specific mutations (Brannon et al 2014;Tan et al 2015).…”

Individualised multiplexed circulating tumour DNA assays for monitoring of tumour presence in patients after colorectal cancer surgery

“…In particular, we wanted to be able to simultaneously assay for the presence of multiple somatic mutations identified from the CRC primary tumour in patient plasma and determine the correlation with clinical events. In CRC, because of the high degree of genomic similarity of the primary and metastases1011, the resected surgical specimen provides an available mutational profile to monitor and or provide diagnostic support for the recurrence of the same cancer. Similar studies have recently shown that ctDNA can be detected in CRC patients post-surgery.…”

“…Previous studies that used tumour tissue to determine mutations to monitor in ctDNA used tissue fairly contemporary to the plasma assayed. However, we and others showed that there is a large degree of genomic concordance amongst somatic mutations (about 80%) in each patient’s primary tumour and corresponding metastatic lesion1011. This suggested that we could indeed use somatic mutations identified from a patient’s surgical primary CRC specimen to provide an individualised “nucleic acid thumbprint” for detection in plasma at metastasis, specific not only to the patient, but also to the particular cancer.…”

Genetic alterations in Japanese extrahepatic biliary tract cancer

“…Two of the four mutations (p.D351H and p.R361H) are well-known pathological mutations, and the other two missense mutations (p.G352E and p.A532D) are relatively infrequent mutations. The presence of p.G352E was reported in colorectal cancer (32), squamous cell lung cancer (33) and pancreatic cancer in the COSMIC (v74) database (34); p.A532D was identified in colorectal and pancreatic cancer in the COSMIC (v74) database (35). These two mutations were identified as pathological mutations following in silico analysis, including SIFT, PolyPhen and PANTHER.…”