Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

Whole-genome reconstruction and mutational signatures in gastric cancer

Niranjan Nagarajan et al. Genome Biol. .

Abstract

Background: Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability.

Results: Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer.

Conclusions: These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Copy number of two gastric cancer genomes, mechanism of 12p amplification and creation of a fusion gene. (a) Somatic CNVs in the two gastric tumors (chromosomes are arranged on the x-axis, copy number is shown on the y-axis). (b) Copy number of chromosome 12 (top) and the amplicon on 12p (middle) are shown in orange (y-axis). Rearrangements identified by DNA-PET clusters with a size ≥ 45 are represented by arrows and connecting lines (bottom). Dark red and pink arrows represent 5' and 3' cluster regions, respectively, with the connection between the tip of the dark red and the blunt end of the pink arrows. Numbers represent cluster sizes. (c) Fusion between SOX5 and OVCH1 predicted by a rearrangement point with cluster size of 129 in (b).
Figure 2
Figure 2
Map of somatic alterations in two gastric cancer genomes. The Circos plots depict the following information in order from outer to inner rings: using WGS data (1) CNVs (gain in red capped at 10 copies and loss in gray), (2) indel density (indel frequency per 10 kbp in blue, capped at 5 indels/10 kbp), (3) SNV density (SNV frequency per 10 kbp in black, each ring is 5 SNVs/10 kbp, capped at 10), and using DNA-PET data, (4) deletions (in red), tandem duplications (green) and inversions (purple), (5) intra- and (6) inter-chromosomal, insertions (orange) and unpaired SVs (gray).
Figure 3
Figure 3
Genome-wide and exome-wide mutational fingerprint. (a) Frequency of various classes of somatic SNVs genome-wide. (b) Frequency of somatic SNVs exome-wide. (c) Mutational bias as a function of infection status using data from 34 exomes (bias for SNV class i was computed as (si - gi)/gi, where si and gi are the somatic and germline SNV frequencies). Note that nearly identical results were obtained when MSI tumors were excluded from the analysis (*P-value < 0.1; **P-values < 0.01, respectively). (d) Size-distribution of germline and somatic indels genome-wide.
See this image and copyright information in PMC

References

    1. Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci. 2010;13:302–308. - PubMed
    1. Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordonez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;13:184–190. doi: 10.1038/nature08629. - DOI - PMC - PubMed
    1. Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J, Yue P, Zhang Y, Pant KP, Bhatt D, Ha C, Johnson S, Kennemer MI, Mohan S, Nazarenko I, Watanabe C, Sparks AB, Shames DS, Gentleman R, de Sauvage FJ, Stern H, Pandita A, Ballinger DG, Drmanac R, Modrusan Z, Seshagiri S, Zhang Z. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010;13:473–477. doi: 10.1038/nature09004. - DOI - PubMed
    1. Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;13:191–196. doi: 10.1038/nature08658. - DOI - PMC - PubMed
    1. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea S, Gonzalez-Diaz M, Bassaganyas L, Baumann T, Juan M, Lopez-Guerra M, Colomer D, Tubio JM, Lopez C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernandez JM, Puente DA, Freije JM, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes A. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;13:101–105. doi: 10.1038/nature10113. - DOI - PMC - PubMed

Publication types

Substances

Associated data