High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer
High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer
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DOI：
10.1007/s10549-009-0596-6
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发表时间：
2010-08-01
影响因子：
3.8
通讯作者：
Jorge Podesta, Ernesto
中科院分区：
文献类型：
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作者：
Aceto, Gitana Maria;Rosaria Solano, Angela;Jorge Podesta, Ernesto
青少年乳腺癌很少见，也鲜为人知。我们研究了5名25岁以内确诊的乳腺癌患者，其中包括2名青少年，分别为12岁和15岁，以及3名年轻女性，分别为21岁、21岁和25岁。采用蛋白截断法、变性高效液相色谱法和直接测序技术，沿BRCA1/2整个编码序列和TP53 4-10外显子扫描所有病例的种系突变。石蜡包埋的原发肿瘤（4/5例）和远处转移（来自15岁）的组织学和分子肿瘤亚型，人乳头瘤病毒（HPV） 16/18型E6序列和TP53外显子5-8的肿瘤相关突变。一种BRCA2种系突变（p.i ile2490thr），先前在乳腺癌中报道过，在Fanconi贫血中作为复合杂合子，在怀孕后诊断的21岁患者中被发现，癌症家族史阴性。该肿瘤无法用于研究。在其他病例中，仅检测到BRCA1/2和/或TP53的种系多态性。15岁和12岁的肿瘤分别归类为富糖原癌三阴性亚型和分泌性癌基底亚型。25岁的患者和21岁的患者分别被诊断为浸润性导管癌伴腔内A亚型和小叶癌伴腔内B亚型。未发现体细胞TP53突变，但从12岁和25岁的患者中检索到肿瘤相关的HPV 16 E6序列，而在15岁的肿瘤及其相关转移中均发现了HPV 16和HPV 18 E6序列。15岁和25岁的患者被诊断为晚期疾病，他们的血液中HPV 16e6呈阳性。所有hpv阳性病例均为TP53密码子72处精氨酸纯合，这是一种与hpv相关癌症风险相关的基因型，肿瘤显示p16（INK4A）免疫染色，这是hpv相关癌症的标志物。值得注意的是，这两名青少年在11岁时就出现了月经初潮，而25岁的那名是在怀孕和哺乳后确诊的。我们的数据表明，高危HPV感染涉及与初潮或妊娠和母乳喂养相关的组织病理学异质性青少年乳腺癌的一个子集。此外，我们暗示BRCA2在21岁时诊断出的青少年乳腺癌中，在早期足月妊娠4年后，没有癌症家族史。
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.