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

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.