ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers

Abstract

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2-related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations.

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

“…On the other hand, the ERBB2 subtype comprised only of BRCAX tumors (four cases, B14%) (Table 1). This finding is in concordance with the low incidence of ERBB2 amplification in BRCA1/2 mutation carriers described before (Grushko et al, 2002;Lakhani et al, 2002;Palacios et al, 2003;Adem et al, 2004). A significant association was found between most of BRCAX samples (45%) and luminal A phenotype, as seen in previous analyses (Oldenburg et al, 2006;Honrado et al, 2007).…”

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

“…No cases showed amplification of both HER2 and MYC. These results are in contrast to those obtained by Adem et al, 62 who found a high prevalence of MYC duplications (57%) but a low frequency of amplification (8%) among invasive carcinomas from BRCA1/2-deleterious mutation carriers.…”

TBX2 expression is associated with platinum‑sensitivity of ovarian serous carcinoma

“…Further, TBX2 is upregulated in a subset of breast cancer cell lines, and breast tumors with mutations in BRCA1 and BRCA2 (7,(20)(21)(22), which are strongly associated with ovarian serous carcinoma.…”