High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer.
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.
Unit of Molecular Pathology and Genomics, Aging Research Center (CeSI) G. d'Annunzio University Foundation, Via Colle dell'Ara, 66100 Chieti, Italy.
Gitana Maria
GM
Aceto
Angela Rosaria
AR
Solano
Maria Isabel
MI
Neuman
Serena
S
Veschi
Annalisa
A
Morgano
Sara
S
Malatesta
Reinaldo Daniel
RD
Chacon
Carmen
C
Pupareli
Mercedes
M
Lombardi
Pasquale
P
Battista
Antonio
A
Marchetti
Renato
R
Mariani-Costantini
Ernesto Jorge
EJ
Podestà
D000293:Adolescent; D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology / Q000821:virology; D018275:Carcinoma, Lobular / Q000235:genetics / Q000473:pathology / Q000821:virology; D002648:Child; D017931:DNA Primers / Q000737:chemistry / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D010051:Ovarian Neoplasms / Q000235:genetics / Q000556:secondary / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D017931:DNA Primers; D004279:DNA, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53