Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas

Lisa C. Flowers, Ignacio I. Wistuba, James Scurry, Carolyn Y. Muller, Raheela Ashfaq, David S. Miller, John D. Minna, Adi F. Gazdar

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. Methods: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. Results: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). Conclusion: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers. Copyright (C) 1999 Society for Gynecologic Investigation.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalJournal of the Society for Gynecologic Investigation
Volume6
Issue number4
DOIs
StatePublished - Jul 1999

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Carcinoma
Loss of Heterozygosity
p53 Genes
Neoplasms
Mutation
Human papillomavirus 16
Carcinogenesis
Epithelium

Keywords

  • Chromosome 3p
  • Human papillomavirus
  • Loss of heterozygosity
  • Vulvar cancer

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas. / Flowers, Lisa C.; Wistuba, Ignacio I.; Scurry, James; Muller, Carolyn Y.; Ashfaq, Raheela; Miller, David S.; Minna, John D.; Gazdar, Adi F.

In: Journal of the Society for Gynecologic Investigation, Vol. 6, No. 4, 07.1999, p. 213-221.

Research output: Contribution to journalArticle

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title = "Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas",
abstract = "Objective: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. Methods: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. Results: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80{\%}) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20{\%}), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62{\%} versus 15{\%}; P = .02). Conclusion: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers. Copyright (C) 1999 Society for Gynecologic Investigation.",
keywords = "Chromosome 3p, Human papillomavirus, Loss of heterozygosity, Vulvar cancer",
author = "Flowers, {Lisa C.} and Wistuba, {Ignacio I.} and James Scurry and Muller, {Carolyn Y.} and Raheela Ashfaq and Miller, {David S.} and Minna, {John D.} and Gazdar, {Adi F.}",
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T1 - Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas

AU - Flowers, Lisa C.

AU - Wistuba, Ignacio I.

AU - Scurry, James

AU - Muller, Carolyn Y.

AU - Ashfaq, Raheela

AU - Miller, David S.

AU - Minna, John D.

AU - Gazdar, Adi F.

PY - 1999/7

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N2 - Objective: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. Methods: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. Results: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). Conclusion: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers. Copyright (C) 1999 Society for Gynecologic Investigation.

AB - Objective: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. Methods: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. Results: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). Conclusion: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers. Copyright (C) 1999 Society for Gynecologic Investigation.

KW - Chromosome 3p

KW - Human papillomavirus

KW - Loss of heterozygosity

KW - Vulvar cancer

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