Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples

George Vasmatzis, Xue Wang, James Smadbeck, Stephen J. Murphy, Katherine B. Geiersbach, Sarah H. Johnson, Athanasios G. Gaitatzes, Yan Asmann, Farhad Kosari, Mitesh J Borad, Daniel J. Serie, Sarah A. McLaughlin, Jennifer M. Kachergus, Brian M. Necela, E Aubrey Thompson

Research output: Contribution to journalArticle

Abstract

Background: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. Methods: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. Results: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. Conclusion: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events.

Original languageEnglish (US)
Article number738
JournalBMC Cancer
Volume18
Issue number1
DOIs
StatePublished - Jul 13 2018

Fingerprint

Chromosomes, Human, Pair 8
Breast Neoplasms
Chromosomes, Human, Pair 17
Transcriptome
Genome
Mutation
Neoplasms

Keywords

  • Amplification
  • Chromoanagenesis
  • Chromoanasynthesis
  • Chromodesmy
  • Chromoplexy
  • Chromothripsis
  • Neochromosome
  • Replication

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples. / Vasmatzis, George; Wang, Xue; Smadbeck, James; Murphy, Stephen J.; Geiersbach, Katherine B.; Johnson, Sarah H.; Gaitatzes, Athanasios G.; Asmann, Yan; Kosari, Farhad; Borad, Mitesh J; Serie, Daniel J.; McLaughlin, Sarah A.; Kachergus, Jennifer M.; Necela, Brian M.; Thompson, E Aubrey.

In: BMC Cancer, Vol. 18, No. 1, 738, 13.07.2018.

Research output: Contribution to journalArticle

Vasmatzis, George ; Wang, Xue ; Smadbeck, James ; Murphy, Stephen J. ; Geiersbach, Katherine B. ; Johnson, Sarah H. ; Gaitatzes, Athanasios G. ; Asmann, Yan ; Kosari, Farhad ; Borad, Mitesh J ; Serie, Daniel J. ; McLaughlin, Sarah A. ; Kachergus, Jennifer M. ; Necela, Brian M. ; Thompson, E Aubrey. / Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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abstract = "Background: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. Methods: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. Results: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. Conclusion: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events.",
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T1 - Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples

AU - Vasmatzis, George

AU - Wang, Xue

AU - Smadbeck, James

AU - Murphy, Stephen J.

AU - Geiersbach, Katherine B.

AU - Johnson, Sarah H.

AU - Gaitatzes, Athanasios G.

AU - Asmann, Yan

AU - Kosari, Farhad

AU - Borad, Mitesh J

AU - Serie, Daniel J.

AU - McLaughlin, Sarah A.

AU - Kachergus, Jennifer M.

AU - Necela, Brian M.

AU - Thompson, E Aubrey

PY - 2018/7/13

Y1 - 2018/7/13

N2 - Background: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. Methods: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. Results: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. Conclusion: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events.

AB - Background: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. Methods: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. Results: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. Conclusion: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events.

KW - Amplification

KW - Chromoanagenesis

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KW - Chromodesmy

KW - Chromoplexy

KW - Chromothripsis

KW - Neochromosome

KW - Replication

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