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Case Reports
. 2014 Jan 9:7:2.
doi: 10.1186/1755-8794-7-2.

Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas

Limei Ouyang, Jeeyun Lee, Cheol-Keun Park, Mao Mao, Yujian Shi, Zhuolin Gong, Hancheng Zheng, Yingrui Li, Yonggang Zhao, Guangbiao Wang, Huiling Fu, Jhingook Kim  1 , Ho Yeong Lim
Affiliations
Case Reports

Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas

Limei Ouyang et al. BMC Med Genomics. .

Abstract

Background: To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases.

Methods: We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval).

Results: In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65-221 structural variations (SVs) in primary tumors and 60-232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis.

Conclusions: We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments.

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Figures

Figure 1
Figure 1
Circos plots for the 4 primary tumors and their matched metastases. Outer panels represent somatic SNVs with nonsynonymous and splice mutations in red, others are in black. Somatic copy number alterations are shown in inner panels (orange histogram, duplications; blue histogram, deletions). Structural variations are depicted as links in the interior of the plots. Blue link, inter-chromosomal translocations; red link, intra-chromosomal translocations; purple link, insertions; green link, deletions. Plots of A to H show the variants of primary tumor and metastasis from each of the 4 cases 441, D430, D473 and DD59 with “P” for primary and “M” for metastasis.
Figure 2
Figure 2
The number of somatic mutations detected in primary tumors and metastases. The percentage of mutations shared by metastases and primary tumors was calculated, and the mutations are summarized into 3 groups: primary tumors, metastases, and shared mutations.
Figure 3
Figure 3
Comparison of mutational classes between primary tumors and metastasis samples. (A) The transition and transversion categories of coding mutations are classified from primary tumor and metastasis-specific groups. (B) Fraction of overall mutations spanning the transition and transversion categories are concluded in primary tumor and metastasis-specific groups. Red boxes represent primary tumor and blue boxes represent metastasis. Asterisks represent significant difference between primary tumor and metastasis (*, 1e-3<P ≤ 5e-2; **, 1e-10<P ≤ 1e-3; ***, P ≤ 1e-10).
Figure 4
Figure 4
Comparison of nonsynonymous and splice mutation frequency between primary tumors and metastases. Each point represents a somatic single-nucleotide variant (SNV). Allele frequency enrichment was tested using the Fishers’ exact test. Gray dot, shared mutations; orange, significantly enriched mutations in primary tumors; green, significantly enriched mutations in metastases; purple, primary tumor-specific mutations; blue, metastasis-specific mutations. SNVs in cancer genes or genes located in cancer-related pathways are labeled with the corresponding gene names. SNVs in each of the 4 cases show in plots A to D separately.
Figure 5
Figure 5
Significantly altered pathway in primary tumor. Pathway analysis for primary tumor mutant genes identified significant genomic alteration in several cancer pathways, including (A) Wnt, (B) focal adhesion, (C) JAK-STAT and (D) cell cycle pathways. Alterations included somatic SNVs, Indels, CNAs and SVs. Alteration recurrence was referred as number of cases harboring a mutant gene. Alteration types were represented by different colours.
Figure 6
Figure 6
Significantly altered pathway in metastasis. Pathway analysis for metastasis-specific mutant genes identified significant genomic alteration in multiple cancer/cell migration relevant pathways, including (A) tight junction, (B) ErbB/MAPK and (C) focal adhesion pathway. Alterations included somatic SNVs, Indels, CNAs and SVs. Alteration recurrence was referred as number of cases harboring a mutant gene. Alteration types were represented by different colours.
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References

    1. El-Serag HBRK. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;7:2557–2576. doi: 10.1053/j.gastro.2007.04.061. - DOI - PubMed
    1. Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;7:1893–1907. doi: 10.1158/1055-9965.EPI-10-0437. - DOI - PubMed
    1. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the human development index (2008–2030): a population-based study. Lancet Oncol. 2012;7:790–801. doi: 10.1016/S1470-2045(12)70211-5. - DOI - PubMed
    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;7:69–90. doi: 10.3322/caac.20107. - DOI - PubMed
    1. Rahbari NNMA, Mollberg NM, Müller SA, Koch M, Büchler MW, Weitz J. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 2011;7:453–469. doi: 10.1097/SLA.0b013e31820d944f. - DOI - PubMed

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