Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data

Groep, Petra van der; Bouter, A; Zanden, Rianne van der; Siccama, Ivar; Menko, Fred H.; Gille, Johan J. P.; Kalken, C van; Wall, Elsken van der; Verheijen, René H.M.; Diest, Paul J. van

doi:10.1136/jcp.2005.032151

Cited by 80 publications

(64 citation statements)

References 28 publications

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“…They often concern well demarcated medullary and poorly differentiated ductal cancers with conspicuous lymphocytoplasmic infiltrates [9,10] that are of high-grade [11] and show high proliferation [12]. In addition, they do not express estrogen (ER), progesterone (PR) or HER-2/neu receptors [13], often lack p27 Kip1 [14], but do accumulate p53 [15], and overexpress cyclin E [16], cytokeratins (CK) 5/6 and 14 [17,18], and EGFR [19][20][21]. These observations point to a carcinogenetic pathway of BRCA1 related breast cancers different from that in sporadic cancers.…”

Section: Introductionmentioning

confidence: 99%

High frequency of HIF-1α overexpression in BRCA1 related breast cancer

Groep

Bouter

Menko

et al. 2007

Breast Cancer Res Treat

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Hypoxia is a hallmark of cancer. Hypoxia inducible factor-1alpha (HIF-1alpha) is the key regulator of the hypoxia response. HIF-1alpha is overexpressed during sporadic breast carcinogenesis and correlated with poor prognosis. Little is known on the role of HIF-1alpha in hereditary breast carcinogenesis. A recent study suggests a role for BRCA1 in HIF-1alpha regulation. We therefore examined the expression of HIF-1alpha in BRCA1 related breast cancers. By immunohistochemistry we studied expression of HIF-1alpha and some of its downstream targets in 30 hereditary invasive breast cancers in comparison with 200 sporadic controls. HIF-1alpha overexpression was significantly more frequent in BRCA1 related breast cancers (27/30, 90%) than in sporadic controls (88/200, 44%) (P < 0.0001). 19/30 (63%) of BRCA1 tumors showed perinecrotic (hypoxia induced) and 8/30 (27%) a diffuse HIF-1alpha overexpression pattern, the latter more likely related to genetic alterations in oncogenes and tumor suppressor genes. In contrast, sporadic breast cancer HIF-1 expressing tumors showed an inverse ratio of perinecrotic/diffuse expression (31 vs. 69%, P = 0.0002). Glut-1 and CAIX, downstream HIF1 targets, were expressed in 27/30 (90%) and 15/21 (71%) of hereditary cases versus 54/183 (29%) and 24/183 (13%) in sporadic cases. p300 levels, necessary for HIF-1 downstream activation, were significantly higher in hereditary cases (20/21, 95%) compared to sporadic cases (91/183, 50%, P = 0.0001). In conclusion, in BRCA1 germline mutation related breast cancer, functional HIF-1alpha overexpression is seen at a much higher frequency than in sporadic breast cancer, mostly hypoxia induced. This points to an important role of hypoxia and its key regulator HIF-1alpha in hereditary breast carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

High frequency of HIF-1α overexpression in BRCA1 related breast cancer

Groep

Bouter

Menko

et al. 2007

Breast Cancer Res Treat

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“…This gene is responsible for most cases of hereditary breast and ovarian cancer. BRCA1-associated cancers are typically high grade and TN, and share common pathologic features such as positive EGFR immunostaining [67][68][69]; also, Foulkes et al [61] found that the majority of these BRCA1-associated cancers that are ER negative (81%) are more likely to develop at a younger age (before age 45), compared to 62% of cancers in women diagnosed after age 65. Furthermore, the proportion of BRCA1-associated cancers that are of the basal phenotype has been estimated to be 88% and 57% by Foulkes et al [61] and Lakhani et al [67], respectively.…”

Section: Definition and Risk Factors Of Tnbcmentioning

confidence: 99%

Triple-Negative Breast Cancer: Clinical and Histological Correlations

Elsawaf

Sinn²

2011

Breast Care

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Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptors and the lack of HER2 expression or amplification. Much interest has recently been focused on these triple-negative (TN) subtypes because they may be aggressive and are more likely to recur and metastasize than other subtypes of breast cancer. TNBC accounts for approximately 10–24% of all breast cancer cases, and typically it occurs in younger patients and in patients with BRCA1 mutation. There is a substantial heterogeneity of TNBCs both at the morphological and the molecular level, but there are also common features, such as low tumor grade and accelerated tumor proliferation. Morphologically, TNBC may present as invasive ductal, metaplastic, medullary, apocrine, or other types. Molecularly, they are most frequently associated with a basal phenotype, but there is a distinct subgroup of cancers that are not of basal type and belong to the claudin-low or molecular-apocrine type. The basal phenotype is frequently associated with the loss of BRCA1.

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“…This phenotype has high grade, is ER/PR/ HER2 negative, often of typical or atypical medullar histology, and expresses cytokeratin 5/6, cyclin E, and epidermal growth factor receptor (8 -10). Expression of basal keratins cytokeratin 14 and cytokeratin 5/6, together with ER status, seems to be predictive for BRCA1 mutation status compared with sporadic breast tumors (11).In most studies to date, BRCA2-associated tumors have shown a phenotype between the BRCA1-associated and sporadic tumors (4,5,12). cDNA studies, however, identify a distinct expression profile for BRCA2 tumors (13).…”

mentioning

confidence: 99%

“…In most studies to date, BRCA2-associated tumors have shown a phenotype between the BRCA1-associated and sporadic tumors (4,5,12). cDNA studies, however, identify a distinct expression profile for BRCA2 tumors (13).…”

mentioning

confidence: 99%

Familial Breast Cancers without Mutations in BRCA1 or BRCA2 Have Low Cyclin E and High Cyclin D1 in Contrast to Cancers in BRCA Mutation Carriers

Aaltonen

Blomqvist²,

Amini

et al. 2008

Clinical Cancer Research

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Purpose: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation^negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1expression has not been studied. Experimental Design: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. Results: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. Conclusions: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1-and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.High-penetrance predisposition genes cause 5% to 10% of breast cancer. The two major high-penetrance susceptibility genes BRCA1 and BRCA2 account together for f20% of familial breast cancers in Finland (1). Cancers in carriers of BRCA1 and BRCA2 mutations differ from sporadic and familial non-BRCA1/2 cancers. BRCA1-associated tumors are of higher tumor grade; more often estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative, and p53 positive; and more often of medullary histology than sporadic cancers (2 -6).cDNA expression analysis suggests that the basal cell epithelial phenotype is overrepresented in tumors of BRCA1 mutation carriers (7). This phenotype has high grade, is ER/PR/ HER2 negative, often of typical or atypical medullar histology, and expresses cytokeratin 5/6, cyclin E, and epidermal growth factor receptor (8 -10). Expression of basal keratins cytokeratin 14 and cytokeratin 5/6, together with ER status, seems to be predictive for BRCA1 mutation status compared with sporadic breast tumors (11).In most studies to date, BRCA2-associated tumors have shown a phenotype between the BRCA1-associated and sporadic tumors (4,5,12). cDNA studies, however, identify a di...

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Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data

Abstract: Breast carcinomas can be classified with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR. This can be clinically useful in mutation analysis in families with a borderline risk of hereditary disease.

Cited by 80 publications

References 28 publications

High frequency of HIF-1α overexpression in BRCA1 related breast cancer

High frequency of HIF-1α overexpression in BRCA1 related breast cancer

Triple-Negative Breast Cancer: Clinical and Histological Correlations

Familial Breast Cancers without Mutations in BRCA1 or BRCA2 Have Low Cyclin E and High Cyclin D1 in Contrast to Cancers in BRCA Mutation Carriers

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