Identification of submicroscopic genetic changes and precise breakpoint mapping in myelofibrosis using high resolution mate-pair sequencing

Terra Lasho, Sarah H. Johnson, David I Smith, John D. Crispino, Animesh D Pardanani, George Vasmatzis, Ayalew Tefferi

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Abstract

We used high resolution mate-pair sequencing (HRMPS) in 15 patients with primary myelofibrosis (PMF): eight with normal karyotype and seven with PMF-characteristic cytogenetic abnormalities, including der(6)t(1;6)(q21-23;p21.3) (n=4), der(7)t(1;7)(q10;p10) (n=2), del(20)(q11.2q13.3) (n=3), and complex karyotype (n=1). We describe seven novel deletions/translocations in five patients (including two with normal karyotype) whose breakpoints were PCR-validated and involved MACROD2, CACNA2D4, TET2, SGMS2, LRBA, SH3D19, INTS3, FOP (CHTOP), SCLT1, and PHF17. Deletions with breakpoints involving MACROD2 (lysine deacetylase; 20p12.1) were recurrent and found in two of the 15 study patients. A novel fusion transcript was found in one of the study patients (INTS3-CHTOP), and also in an additional non-study patient with PMF. In two patients with der(6)t(1;6)(q21-23;p21.3), we were able to map the precise translocation breakpoints, which involved KCNN3 and GUSBP2 in one case and HYDIN2 in another. This study demonstrates the utility of HRMPS in uncovering submicroscopic deletions/translocations/fusions, and precise mapping of breakpoints in those with overt cytogenetic abnormalities. The overall results confirm the genetic heterogeneity of PMF, given the low frequency of recurrent specific abnormalities, identified by this screening strategy. Currently, we are pursuing the pathogenetic relevance of some of the aforementioned findings.

Original languageEnglish (US)
Pages (from-to)741-746
Number of pages6
JournalAmerican Journal of Hematology
Volume88
Issue number9
DOIs
StatePublished - Sep 2013

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Primary Myelofibrosis
Karyotype
Chromosome Aberrations
Genetic Heterogeneity
Lysine
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Hematology

Cite this

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title = "Identification of submicroscopic genetic changes and precise breakpoint mapping in myelofibrosis using high resolution mate-pair sequencing",
abstract = "We used high resolution mate-pair sequencing (HRMPS) in 15 patients with primary myelofibrosis (PMF): eight with normal karyotype and seven with PMF-characteristic cytogenetic abnormalities, including der(6)t(1;6)(q21-23;p21.3) (n=4), der(7)t(1;7)(q10;p10) (n=2), del(20)(q11.2q13.3) (n=3), and complex karyotype (n=1). We describe seven novel deletions/translocations in five patients (including two with normal karyotype) whose breakpoints were PCR-validated and involved MACROD2, CACNA2D4, TET2, SGMS2, LRBA, SH3D19, INTS3, FOP (CHTOP), SCLT1, and PHF17. Deletions with breakpoints involving MACROD2 (lysine deacetylase; 20p12.1) were recurrent and found in two of the 15 study patients. A novel fusion transcript was found in one of the study patients (INTS3-CHTOP), and also in an additional non-study patient with PMF. In two patients with der(6)t(1;6)(q21-23;p21.3), we were able to map the precise translocation breakpoints, which involved KCNN3 and GUSBP2 in one case and HYDIN2 in another. This study demonstrates the utility of HRMPS in uncovering submicroscopic deletions/translocations/fusions, and precise mapping of breakpoints in those with overt cytogenetic abnormalities. The overall results confirm the genetic heterogeneity of PMF, given the low frequency of recurrent specific abnormalities, identified by this screening strategy. Currently, we are pursuing the pathogenetic relevance of some of the aforementioned findings.",
author = "Terra Lasho and Johnson, {Sarah H.} and Smith, {David I} and Crispino, {John D.} and Pardanani, {Animesh D} and George Vasmatzis and Ayalew Tefferi",
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T1 - Identification of submicroscopic genetic changes and precise breakpoint mapping in myelofibrosis using high resolution mate-pair sequencing

AU - Lasho, Terra

AU - Johnson, Sarah H.

AU - Smith, David I

AU - Crispino, John D.

AU - Pardanani, Animesh D

AU - Vasmatzis, George

AU - Tefferi, Ayalew

PY - 2013/9

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N2 - We used high resolution mate-pair sequencing (HRMPS) in 15 patients with primary myelofibrosis (PMF): eight with normal karyotype and seven with PMF-characteristic cytogenetic abnormalities, including der(6)t(1;6)(q21-23;p21.3) (n=4), der(7)t(1;7)(q10;p10) (n=2), del(20)(q11.2q13.3) (n=3), and complex karyotype (n=1). We describe seven novel deletions/translocations in five patients (including two with normal karyotype) whose breakpoints were PCR-validated and involved MACROD2, CACNA2D4, TET2, SGMS2, LRBA, SH3D19, INTS3, FOP (CHTOP), SCLT1, and PHF17. Deletions with breakpoints involving MACROD2 (lysine deacetylase; 20p12.1) were recurrent and found in two of the 15 study patients. A novel fusion transcript was found in one of the study patients (INTS3-CHTOP), and also in an additional non-study patient with PMF. In two patients with der(6)t(1;6)(q21-23;p21.3), we were able to map the precise translocation breakpoints, which involved KCNN3 and GUSBP2 in one case and HYDIN2 in another. This study demonstrates the utility of HRMPS in uncovering submicroscopic deletions/translocations/fusions, and precise mapping of breakpoints in those with overt cytogenetic abnormalities. The overall results confirm the genetic heterogeneity of PMF, given the low frequency of recurrent specific abnormalities, identified by this screening strategy. Currently, we are pursuing the pathogenetic relevance of some of the aforementioned findings.

AB - We used high resolution mate-pair sequencing (HRMPS) in 15 patients with primary myelofibrosis (PMF): eight with normal karyotype and seven with PMF-characteristic cytogenetic abnormalities, including der(6)t(1;6)(q21-23;p21.3) (n=4), der(7)t(1;7)(q10;p10) (n=2), del(20)(q11.2q13.3) (n=3), and complex karyotype (n=1). We describe seven novel deletions/translocations in five patients (including two with normal karyotype) whose breakpoints were PCR-validated and involved MACROD2, CACNA2D4, TET2, SGMS2, LRBA, SH3D19, INTS3, FOP (CHTOP), SCLT1, and PHF17. Deletions with breakpoints involving MACROD2 (lysine deacetylase; 20p12.1) were recurrent and found in two of the 15 study patients. A novel fusion transcript was found in one of the study patients (INTS3-CHTOP), and also in an additional non-study patient with PMF. In two patients with der(6)t(1;6)(q21-23;p21.3), we were able to map the precise translocation breakpoints, which involved KCNN3 and GUSBP2 in one case and HYDIN2 in another. This study demonstrates the utility of HRMPS in uncovering submicroscopic deletions/translocations/fusions, and precise mapping of breakpoints in those with overt cytogenetic abnormalities. The overall results confirm the genetic heterogeneity of PMF, given the low frequency of recurrent specific abnormalities, identified by this screening strategy. Currently, we are pursuing the pathogenetic relevance of some of the aforementioned findings.

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