Breast Cancer Research and Treatment

, Volume 122, Issue 3, pp 671–683 | Cite as

High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer

  • Gitana Maria Aceto
  • Angela Rosaria Solano
  • Maria Isabel Neuman
  • Serena Veschi
  • Annalisa Morgano
  • Sara Malatesta
  • Reinaldo Daniel Chacon
  • Carmen Pupareli
  • Mercedes Lombardi
  • Pasquale Battista
  • Antonio Marchetti
  • Renato Mariani-Costantini
  • Ernesto Jorge Podestà
Preclinical study

Abstract

Juvenile breast cancer is rare and poorly known. We studied a series of five breast cancer patients diagnosed within 25 years of age that included two adolescents, 12- and 15-years-old, and 3 young women, 21-, 21-, and 25-years-old, respectively. All cases were scanned for germline mutations along the entire BRCA1/2 coding sequences and TP53 exons 4–10, using protein truncation test, denaturing high performance liquid chromatography and direct sequencing. Paraffin-embedded primary tumors (available for 4/5 cases), and a distant metastasis (from the 15-years-old) were characterized for histological and molecular tumor subtype, human papilloma virus (HPV) types 16/18 E6 sequences and tumor-associated mutations in TP53 exons 5–8. A BRCA2 germline mutation (p.Ile2490Thr), previously reported in breast cancer and, as compound heterozygote, in Fanconi anemia, was identified in the 21-year-old patient diagnosed after pregnancy, negative for cancer family history. The tumor was not available for study. Only germline polymorphisms in BRCA1/2 and/or TP53 were detected in the other cases. The tumors of the 15- and 12-years-old were, respectively, classified as glycogen-rich carcinoma with triple negative subtype and as secretory carcinoma with basal subtype. The tumors of the 25-year-old and of the other 21-year-old were, respectively, diagnosed as infiltrating ductal carcinoma with luminal A subtype and as lobular carcinoma with luminal B subtype. No somatic TP53 mutations were found, but tumor-associated HPV 16 E6 sequences were retrieved from the 12- and 25-year-old, while both HPV 16 and HPV 18 E6 sequences were found in the tumor of the 15-year-old and in its associated metastasis. Blood from the 15- and 25-year-old, diagnosed with high-stage disease, resulted positive for HPV 16 E6. All the HPV-positive cases were homozygous for arginine at TP53 codon 72, a genotype associated with HPV-related cancer risk, and the tumors showed p16(INK4A) immunostaining, a marker of HPV-associated cancers. Notably menarche at 11 years was reported for the two adolescents, while the 25-year-old was diagnosed after pregnancy and breast-feeding. Our data suggest that high-risk HPV infection is involved in a subset of histopathologically heterogeneous juvenile breast carcinomas associated with menarche or pregnancy and breast-feeding. Furthermore we implicate BRCA2 in a juvenile breast carcinoma diagnosed at 21 years of age, 4 years after an early full-term pregnancy, in absence of cancer family history.

Keywords

Juvenile breast cancer BRCA1 BRCA2 TP53 Mutation Human papilloma virus Reproductive factors 

HPV in juvenile breast cancer

BC

Breast cancer

jBC

Juvenile breast cancer

HPV

Human papilloma virus

HRDC

Laboratorio de Hormonas en la Regulacion y Diferenciacion Celular

PAS

Periodic acid-Schiff

ER

Estrogen receptor

PgR

Progesterone receptor

CK5

Cytokeratin 5

SMA

Smooth muscle actin

PTT

Protein truncation test

DHPLC

Denaturing high performance liquid chromatography

HGVS

Human Genome Variation Society

PCR

Polymerase chain reaction

BIC

Breast Cancer Information Core

pRb

Retinoblastoma protein

p16(INK4A)

Cyclin-dependent kinase-4 inhibitor

IARC

International Agency for Research on Cancer

Supplementary material

10549_2009_596_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Gitana Maria Aceto
    • 1
    • 3
  • Angela Rosaria Solano
    • 4
  • Maria Isabel Neuman
    • 4
  • Serena Veschi
    • 1
    • 2
    • 3
  • Annalisa Morgano
    • 1
    • 2
  • Sara Malatesta
    • 5
  • Reinaldo Daniel Chacon
    • 6
  • Carmen Pupareli
    • 6
  • Mercedes Lombardi
    • 7
  • Pasquale Battista
    • 3
  • Antonio Marchetti
    • 5
  • Renato Mariani-Costantini
    • 1
    • 2
  • Ernesto Jorge Podestà
    • 4
  1. 1.Unit of Molecular Pathology and GenomicsAging Research Center (CeSI) G. d’Annunzio University FoundationChietiItaly
  2. 2.Department of Oncology and NeurosciencesG. d’Annunzio UniversityChietiItaly
  3. 3.Department of Human Movement SciencesG. d’Annunzio UniversityChietiItaly
  4. 4.Laboratorio de Hormonas en la Regulacion y Diferenciacion Celular (HRDC), Instituto de Investigaciones Moleculares de Enfermedades Hormonales Neurodegenerativas y Oncologicas (IIMHNO), Departamento de Bioquímica, Facultad de MedicinaUniversidad de Buenos AiresCiudad de Buenos AiresArgentina
  5. 5.Unit of Molecular PathologyClinical Research Center (CRC), CeSI, G. d’Annunzio University FoundationChietiItaly
  6. 6.Instituto Alexander FlemingCiudad de Buenos AiresArgentina
  7. 7.Hospital de Niños “Dr. Ricardo Gutierrez”Ciudad de Buenos AiresArgentina

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