Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

Jennifer Dunlap, Claudia Le, Arielle Shukla, Janice Patterson, Ajia Presnell, Michael Heinrich, Christopher Corless, Megan Troxell

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Mutationally activated protein kinases are appealing therapeutic targets in breast carcinoma. Mutations in phosphatidylinositol-3-kinase (P13KCA) have been described in 8 - 40% of invasive breast carcinomas, and AKT1 mutations have been characterized in 1 - 8% of breast carcinomas. However, there is little data on these mutations in breast precursor lesions. To further delineate the molecular evolution of breast tumorigenesis, samples of invasive breast carcinoma with an accompanying in situ component were macro dissected from formalin-fixed paraffin embedded tissue and screened for mutations in PIK3CA exons 7, 9, 20, and AKT1 exon 2. Laser capture micro dissection (LCM) was performed on mutationpositive carcinomas to directly compare the genotypes of separated invasive and in situ tumor cells. Among 81 cases of invasive carcinoma, there were eight mutations in PIK3CA exon 20 (7 H1047R, 1 H1047L) and four mutations in exon 9 (2 E545K, 1 E542K, 1 E545G), totaling 12/81 (14.8%). In 11 cases examined, paired LCM in situ tumor showed the identical P1K3CA mutation in invasive and in situ carcinoma. Likewise, 3 of 78 (3.8%) invasive carcinomas showed an AKT1 E17K mutation, and this mutation was identified in matching in situ carcinoma in both informative cases. Mutational status did not correlate with clinical parameters including hormone receptor status, grade, and lymph node status. The complete concordance of PIK3CA and AKT1 mutations in matched samples of invasive and in situ tumor indicates that these mutations occur early in breast cancer development and has implications with regard to therapeutics targeted to the PI3 kinase pathway.

Original languageEnglish (US)
Pages (from-to)409-418
Number of pages10
JournalBreast Cancer Research and Treatment
Volume120
Issue number2
DOIs
StatePublished - Apr 2010

Fingerprint

Phosphatidylinositol 3-Kinase
Breast Neoplasms
Mutation
Exons
Carcinoma in Situ
Carcinoma
Dissection
Breast
Lasers
Neoplasms
Molecular Evolution
Phosphatidylinositol 3-Kinases
Paraffin
Protein Kinases
Formaldehyde
Carcinogenesis

Keywords

  • AKT1
  • Breast carcinoma
  • Carcinoma in situ
  • Laser capture microdissection
  • Phosphatidylinositol-3-kinase (pik3ca)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. / Dunlap, Jennifer; Le, Claudia; Shukla, Arielle; Patterson, Janice; Presnell, Ajia; Heinrich, Michael; Corless, Christopher; Troxell, Megan.

In: Breast Cancer Research and Treatment, Vol. 120, No. 2, 04.2010, p. 409-418.

Research output: Contribution to journalArticle

Dunlap, Jennifer ; Le, Claudia ; Shukla, Arielle ; Patterson, Janice ; Presnell, Ajia ; Heinrich, Michael ; Corless, Christopher ; Troxell, Megan. / Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. In: Breast Cancer Research and Treatment. 2010 ; Vol. 120, No. 2. pp. 409-418.
@article{a00b69670de64d15b121d16e2bfefc7b,
title = "Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma",
abstract = "Mutationally activated protein kinases are appealing therapeutic targets in breast carcinoma. Mutations in phosphatidylinositol-3-kinase (P13KCA) have been described in 8 - 40{\%} of invasive breast carcinomas, and AKT1 mutations have been characterized in 1 - 8{\%} of breast carcinomas. However, there is little data on these mutations in breast precursor lesions. To further delineate the molecular evolution of breast tumorigenesis, samples of invasive breast carcinoma with an accompanying in situ component were macro dissected from formalin-fixed paraffin embedded tissue and screened for mutations in PIK3CA exons 7, 9, 20, and AKT1 exon 2. Laser capture micro dissection (LCM) was performed on mutationpositive carcinomas to directly compare the genotypes of separated invasive and in situ tumor cells. Among 81 cases of invasive carcinoma, there were eight mutations in PIK3CA exon 20 (7 H1047R, 1 H1047L) and four mutations in exon 9 (2 E545K, 1 E542K, 1 E545G), totaling 12/81 (14.8{\%}). In 11 cases examined, paired LCM in situ tumor showed the identical P1K3CA mutation in invasive and in situ carcinoma. Likewise, 3 of 78 (3.8{\%}) invasive carcinomas showed an AKT1 E17K mutation, and this mutation was identified in matching in situ carcinoma in both informative cases. Mutational status did not correlate with clinical parameters including hormone receptor status, grade, and lymph node status. The complete concordance of PIK3CA and AKT1 mutations in matched samples of invasive and in situ tumor indicates that these mutations occur early in breast cancer development and has implications with regard to therapeutics targeted to the PI3 kinase pathway.",
keywords = "AKT1, Breast carcinoma, Carcinoma in situ, Laser capture microdissection, Phosphatidylinositol-3-kinase (pik3ca)",
author = "Jennifer Dunlap and Claudia Le and Arielle Shukla and Janice Patterson and Ajia Presnell and Michael Heinrich and Christopher Corless and Megan Troxell",
year = "2010",
month = "4",
doi = "10.1007/s10549-009-0406-1",
language = "English (US)",
volume = "120",
pages = "409--418",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

AU - Dunlap, Jennifer

AU - Le, Claudia

AU - Shukla, Arielle

AU - Patterson, Janice

AU - Presnell, Ajia

AU - Heinrich, Michael

AU - Corless, Christopher

AU - Troxell, Megan

PY - 2010/4

Y1 - 2010/4

N2 - Mutationally activated protein kinases are appealing therapeutic targets in breast carcinoma. Mutations in phosphatidylinositol-3-kinase (P13KCA) have been described in 8 - 40% of invasive breast carcinomas, and AKT1 mutations have been characterized in 1 - 8% of breast carcinomas. However, there is little data on these mutations in breast precursor lesions. To further delineate the molecular evolution of breast tumorigenesis, samples of invasive breast carcinoma with an accompanying in situ component were macro dissected from formalin-fixed paraffin embedded tissue and screened for mutations in PIK3CA exons 7, 9, 20, and AKT1 exon 2. Laser capture micro dissection (LCM) was performed on mutationpositive carcinomas to directly compare the genotypes of separated invasive and in situ tumor cells. Among 81 cases of invasive carcinoma, there were eight mutations in PIK3CA exon 20 (7 H1047R, 1 H1047L) and four mutations in exon 9 (2 E545K, 1 E542K, 1 E545G), totaling 12/81 (14.8%). In 11 cases examined, paired LCM in situ tumor showed the identical P1K3CA mutation in invasive and in situ carcinoma. Likewise, 3 of 78 (3.8%) invasive carcinomas showed an AKT1 E17K mutation, and this mutation was identified in matching in situ carcinoma in both informative cases. Mutational status did not correlate with clinical parameters including hormone receptor status, grade, and lymph node status. The complete concordance of PIK3CA and AKT1 mutations in matched samples of invasive and in situ tumor indicates that these mutations occur early in breast cancer development and has implications with regard to therapeutics targeted to the PI3 kinase pathway.

AB - Mutationally activated protein kinases are appealing therapeutic targets in breast carcinoma. Mutations in phosphatidylinositol-3-kinase (P13KCA) have been described in 8 - 40% of invasive breast carcinomas, and AKT1 mutations have been characterized in 1 - 8% of breast carcinomas. However, there is little data on these mutations in breast precursor lesions. To further delineate the molecular evolution of breast tumorigenesis, samples of invasive breast carcinoma with an accompanying in situ component were macro dissected from formalin-fixed paraffin embedded tissue and screened for mutations in PIK3CA exons 7, 9, 20, and AKT1 exon 2. Laser capture micro dissection (LCM) was performed on mutationpositive carcinomas to directly compare the genotypes of separated invasive and in situ tumor cells. Among 81 cases of invasive carcinoma, there were eight mutations in PIK3CA exon 20 (7 H1047R, 1 H1047L) and four mutations in exon 9 (2 E545K, 1 E542K, 1 E545G), totaling 12/81 (14.8%). In 11 cases examined, paired LCM in situ tumor showed the identical P1K3CA mutation in invasive and in situ carcinoma. Likewise, 3 of 78 (3.8%) invasive carcinomas showed an AKT1 E17K mutation, and this mutation was identified in matching in situ carcinoma in both informative cases. Mutational status did not correlate with clinical parameters including hormone receptor status, grade, and lymph node status. The complete concordance of PIK3CA and AKT1 mutations in matched samples of invasive and in situ tumor indicates that these mutations occur early in breast cancer development and has implications with regard to therapeutics targeted to the PI3 kinase pathway.

KW - AKT1

KW - Breast carcinoma

KW - Carcinoma in situ

KW - Laser capture microdissection

KW - Phosphatidylinositol-3-kinase (pik3ca)

UR - http://www.scopus.com/inward/record.url?scp=77950691967&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950691967&partnerID=8YFLogxK

U2 - 10.1007/s10549-009-0406-1

DO - 10.1007/s10549-009-0406-1

M3 - Article

C2 - 19418217

AN - SCOPUS:77950691967

VL - 120

SP - 409

EP - 418

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 2

ER -