Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing

Winnie S. Liang, Jessica Aldrich, Sara Nasser, Ahmet Kurdoglu, Lori Phillips, Rebecca Reiman, Jacquelyn McDonald, Tyler Izatt, Alexis Christoforides, Angela Baker, Christine Craig, Jan B. Egan, Dana M. Chase, John H. Farley, Alan H Bryce, Alexander Keith Stewart, Mitesh J Borad, John D. Carpten, David W. Craig, Bradley J. Monk

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective: Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample. Materials and Methods: We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis. Results: We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18. Conclusions: We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.

Original languageEnglish (US)
Pages (from-to)329-338
Number of pages10
JournalInternational Journal of Gynecological Cancer
Volume24
Issue number2
DOIs
StatePublished - Jan 2014

Fingerprint

RNA Sequence Analysis
Human papillomavirus 18
DNA Sequence Analysis
Uterine Cervical Neoplasms
Carcinoma
Neoplasms
Genome
Neoplasm Metastasis
Exome
Lung
Papillomavirus Infections
Point Mutation
Squamous Cell Carcinoma
Chromosomes
RNA
Biopsy
DNA
Genes

Keywords

  • Cervical carcinoma
  • HPV integration
  • Next generation sequencing

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing. / Liang, Winnie S.; Aldrich, Jessica; Nasser, Sara; Kurdoglu, Ahmet; Phillips, Lori; Reiman, Rebecca; McDonald, Jacquelyn; Izatt, Tyler; Christoforides, Alexis; Baker, Angela; Craig, Christine; Egan, Jan B.; Chase, Dana M.; Farley, John H.; Bryce, Alan H; Stewart, Alexander Keith; Borad, Mitesh J; Carpten, John D.; Craig, David W.; Monk, Bradley J.

In: International Journal of Gynecological Cancer, Vol. 24, No. 2, 01.2014, p. 329-338.

Research output: Contribution to journalArticle

Liang, WS, Aldrich, J, Nasser, S, Kurdoglu, A, Phillips, L, Reiman, R, McDonald, J, Izatt, T, Christoforides, A, Baker, A, Craig, C, Egan, JB, Chase, DM, Farley, JH, Bryce, AH, Stewart, AK, Borad, MJ, Carpten, JD, Craig, DW & Monk, BJ 2014, 'Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing', International Journal of Gynecological Cancer, vol. 24, no. 2, pp. 329-338. https://doi.org/10.1097/IGC.0000000000000049
Liang, Winnie S. ; Aldrich, Jessica ; Nasser, Sara ; Kurdoglu, Ahmet ; Phillips, Lori ; Reiman, Rebecca ; McDonald, Jacquelyn ; Izatt, Tyler ; Christoforides, Alexis ; Baker, Angela ; Craig, Christine ; Egan, Jan B. ; Chase, Dana M. ; Farley, John H. ; Bryce, Alan H ; Stewart, Alexander Keith ; Borad, Mitesh J ; Carpten, John D. ; Craig, David W. ; Monk, Bradley J. / Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing. In: International Journal of Gynecological Cancer. 2014 ; Vol. 24, No. 2. pp. 329-338.
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abstract = "Objective: Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample. Materials and Methods: We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis. Results: We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18. Conclusions: We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.",
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AU - Liang, Winnie S.

AU - Aldrich, Jessica

AU - Nasser, Sara

AU - Kurdoglu, Ahmet

AU - Phillips, Lori

AU - Reiman, Rebecca

AU - McDonald, Jacquelyn

AU - Izatt, Tyler

AU - Christoforides, Alexis

AU - Baker, Angela

AU - Craig, Christine

AU - Egan, Jan B.

AU - Chase, Dana M.

AU - Farley, John H.

AU - Bryce, Alan H

AU - Stewart, Alexander Keith

AU - Borad, Mitesh J

AU - Carpten, John D.

AU - Craig, David W.

AU - Monk, Bradley J.

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N2 - Objective: Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample. Materials and Methods: We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis. Results: We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18. Conclusions: We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.

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