Molecular characterization of gallbladder cancer using somatic mutation profiling

Milind Javle, Asif Rashid, Chaitanya Churi, Siddhartha Kar, Mingxin Zuo, Agda Karina Eterovic, Graciela M. Nogueras-Gonzalez, Filip Janku, Rachna T. Shroff, Thomas A. Aloia, Jean Nicholas Vauthey, Steven Curley, Gordon Mills, Ivan Roa

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Gallbladder cancer is relatively uncommon, with a high incidence in certain geographic locations, including Latin America, East and South Asia, and Eastern Europe. Molecular characterization of this disease has been limited, and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n = 72) was examined for the presence of targetable, somatic mutations. All cases were formalin fixed and paraffin embedded (FFPE). Two approaches were used: (a) mass spectroscopy-based profiling for 159 point ("hot spot") mutations in 33 genes commonly involved in solid tumors and (b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hot spot mutations; and 15, for NGS. Fourteen hot spot mutations were identified in 9 cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (n = 2) and ALK (n = 1). On NGS, 26 mutations were noted in 15 cases. TP53 and PI3 kinase pathway (STK11, RICTOR, TSC2) mutations were common. One case had FGF10 amplification, whereas another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular, may be a useful platform for identifying novel mutations for targeted therapy.

Original languageEnglish (US)
Pages (from-to)701-708
Number of pages8
JournalHuman Pathology
Volume45
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Gallbladder Neoplasms
Mutation
Paraffin
Formaldehyde
Eastern Europe
Geographic Locations
Surgical Pathology
Far East
Latin America
Neoplasm Genes
Gene Fusion
Phosphatidylinositol 3-Kinases
Mass Spectrometry
Multivariate Analysis

Keywords

  • DNA sequencing
  • Gallbladder neoplasms
  • Mutational analysis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Javle, M., Rashid, A., Churi, C., Kar, S., Zuo, M., Eterovic, A. K., ... Roa, I. (2014). Molecular characterization of gallbladder cancer using somatic mutation profiling. Human Pathology, 45(4), 701-708. https://doi.org/10.1016/j.humpath.2013.11.001

Molecular characterization of gallbladder cancer using somatic mutation profiling. / Javle, Milind; Rashid, Asif; Churi, Chaitanya; Kar, Siddhartha; Zuo, Mingxin; Eterovic, Agda Karina; Nogueras-Gonzalez, Graciela M.; Janku, Filip; Shroff, Rachna T.; Aloia, Thomas A.; Vauthey, Jean Nicholas; Curley, Steven; Mills, Gordon; Roa, Ivan.

In: Human Pathology, Vol. 45, No. 4, 01.01.2014, p. 701-708.

Research output: Contribution to journalArticle

Javle, M, Rashid, A, Churi, C, Kar, S, Zuo, M, Eterovic, AK, Nogueras-Gonzalez, GM, Janku, F, Shroff, RT, Aloia, TA, Vauthey, JN, Curley, S, Mills, G & Roa, I 2014, 'Molecular characterization of gallbladder cancer using somatic mutation profiling', Human Pathology, vol. 45, no. 4, pp. 701-708. https://doi.org/10.1016/j.humpath.2013.11.001
Javle, Milind ; Rashid, Asif ; Churi, Chaitanya ; Kar, Siddhartha ; Zuo, Mingxin ; Eterovic, Agda Karina ; Nogueras-Gonzalez, Graciela M. ; Janku, Filip ; Shroff, Rachna T. ; Aloia, Thomas A. ; Vauthey, Jean Nicholas ; Curley, Steven ; Mills, Gordon ; Roa, Ivan. / Molecular characterization of gallbladder cancer using somatic mutation profiling. In: Human Pathology. 2014 ; Vol. 45, No. 4. pp. 701-708.
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AU - Rashid, Asif

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AU - Eterovic, Agda Karina

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AU - Shroff, Rachna T.

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AB - Gallbladder cancer is relatively uncommon, with a high incidence in certain geographic locations, including Latin America, East and South Asia, and Eastern Europe. Molecular characterization of this disease has been limited, and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n = 72) was examined for the presence of targetable, somatic mutations. All cases were formalin fixed and paraffin embedded (FFPE). Two approaches were used: (a) mass spectroscopy-based profiling for 159 point ("hot spot") mutations in 33 genes commonly involved in solid tumors and (b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hot spot mutations; and 15, for NGS. Fourteen hot spot mutations were identified in 9 cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (n = 2) and ALK (n = 1). On NGS, 26 mutations were noted in 15 cases. TP53 and PI3 kinase pathway (STK11, RICTOR, TSC2) mutations were common. One case had FGF10 amplification, whereas another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular, may be a useful platform for identifying novel mutations for targeted therapy.

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