Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma

Venkatesh Kancherla, Samir Abdullazade, Matthias S. Matter, Manuela Lanzafame, Luca Quagliata, Guglielmo Roma, Yujin Hoshida, Luigi M. Terracciano, Charlotte K.Y. Ng, Salvatore Piscuoglio

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T > C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.

Original languageEnglish (US)
Article number2
JournalFrontiers in Genetics
Volume9
Issue numberFEB
DOIs
StatePublished - Feb 2 2018
Externally publishedYes

Fingerprint

Hepatocellular Carcinoma
Mutation
Missense Mutation
Neoplasms
Tumor-Infiltrating Lymphocytes
Genetic Heterogeneity
Atlases
Cholestasis
p53 Genes
Virus Diseases
Liver Neoplasms
Genes
Disease-Free Survival
Biomarkers
Genome

Keywords

  • Copy number alterations
  • Mutational signature
  • Oncogenic signature
  • Somatic mutations
  • TP53 mutations

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Kancherla, V., Abdullazade, S., Matter, M. S., Lanzafame, M., Quagliata, L., Roma, G., ... Piscuoglio, S. (2018). Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma. Frontiers in Genetics, 9(FEB), [2]. https://doi.org/10.3389/fgene.2018.00002

Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma. / Kancherla, Venkatesh; Abdullazade, Samir; Matter, Matthias S.; Lanzafame, Manuela; Quagliata, Luca; Roma, Guglielmo; Hoshida, Yujin; Terracciano, Luigi M.; Ng, Charlotte K.Y.; Piscuoglio, Salvatore.

In: Frontiers in Genetics, Vol. 9, No. FEB, 2, 02.02.2018.

Research output: Contribution to journalArticle

Kancherla, V, Abdullazade, S, Matter, MS, Lanzafame, M, Quagliata, L, Roma, G, Hoshida, Y, Terracciano, LM, Ng, CKY & Piscuoglio, S 2018, 'Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma', Frontiers in Genetics, vol. 9, no. FEB, 2. https://doi.org/10.3389/fgene.2018.00002
Kancherla V, Abdullazade S, Matter MS, Lanzafame M, Quagliata L, Roma G et al. Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma. Frontiers in Genetics. 2018 Feb 2;9(FEB). 2. https://doi.org/10.3389/fgene.2018.00002
Kancherla, Venkatesh ; Abdullazade, Samir ; Matter, Matthias S. ; Lanzafame, Manuela ; Quagliata, Luca ; Roma, Guglielmo ; Hoshida, Yujin ; Terracciano, Luigi M. ; Ng, Charlotte K.Y. ; Piscuoglio, Salvatore. / Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma. In: Frontiers in Genetics. 2018 ; Vol. 9, No. FEB.
@article{1fe6acc12b294879953e95eeea95225d,
title = "Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma",
abstract = "The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T > C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.",
keywords = "Copy number alterations, Mutational signature, Oncogenic signature, Somatic mutations, TP53 mutations",
author = "Venkatesh Kancherla and Samir Abdullazade and Matter, {Matthias S.} and Manuela Lanzafame and Luca Quagliata and Guglielmo Roma and Yujin Hoshida and Terracciano, {Luigi M.} and Ng, {Charlotte K.Y.} and Salvatore Piscuoglio",
year = "2018",
month = "2",
day = "2",
doi = "10.3389/fgene.2018.00002",
language = "English (US)",
volume = "9",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",
number = "FEB",

}

TY - JOUR

T1 - Genomic analysis revealed new oncogenic signatures in TP53-mutant hepatocellular carcinoma

AU - Kancherla, Venkatesh

AU - Abdullazade, Samir

AU - Matter, Matthias S.

AU - Lanzafame, Manuela

AU - Quagliata, Luca

AU - Roma, Guglielmo

AU - Hoshida, Yujin

AU - Terracciano, Luigi M.

AU - Ng, Charlotte K.Y.

AU - Piscuoglio, Salvatore

PY - 2018/2/2

Y1 - 2018/2/2

N2 - The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T > C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.

AB - The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T > C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.

KW - Copy number alterations

KW - Mutational signature

KW - Oncogenic signature

KW - Somatic mutations

KW - TP53 mutations

UR - http://www.scopus.com/inward/record.url?scp=85042138369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042138369&partnerID=8YFLogxK

U2 - 10.3389/fgene.2018.00002

DO - 10.3389/fgene.2018.00002

M3 - Article

C2 - 29456550

AN - SCOPUS:85042138369

VL - 9

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

IS - FEB

M1 - 2

ER -