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

Melchor, Lorenzo; Honrado, Emiliano; García, Maria José; Álvarez, Sara; Palacios, José; Osorio, Ana; Nathanson, Katherine L.; Benı́tez, Javier

doi:10.1038/sj.onc.1210975

Cited by 72 publications

(68 citation statements)

References 41 publications

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“…Furthermore, tumors of PALB2 carriers, similar to BRCA1, associate very strongly with the triple-negative (estrogen receptor/progesterone receptor/HER2 negative) and basal-like phenotype. This is not shared by tumors of BRCA2 carriers that correlate strongly with the luminalA subtype, as has also previously been suggested in a gene expression study (40), although also luminalB subtype has been found among BRCA2 tumors (41). In previous studies, only few PALB2 mutation carrier tumors have been studied, mainly for the estrogen receptor, progesterone receptor, or HER2 status, with inconsistent results (11 -15).…”

Section: Discussionsupporting

confidence: 54%

The Breast Cancer Susceptibility Mutation PALB2 1592delT Is Associated with an Aggressive Tumor Phenotype

Heikkinen

Kärkkäinen

Aaltonen

et al. 2009

Clinical Cancer Research

124

103

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Purpose: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival. Experimental Design: We defined the PALB2 mutation status in 947 familial and1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. Results: The PALB2 1592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001] and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5 %; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancer patients.They were also more often of higher grade (P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 (P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up (P = 0.04). Conclusions: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.Breast cancer, the most common cancer among women in the world, has been estimated to have an inherited component of up to 27% (1). Mutations in the two high-penetrance predisposing genes, BRCA1 and BRCA2, are estimated to cause f15% of familial predisposition to breast cancer (2). Based on a meta-analysis, individuals with an inactivating germline mutation in BRCA1 have f57% risk for developing breast cancer and 40% risk for ovarian cancer by the age of 70 years, and individuals with a BRCA2 mutation have 49% risk for breast cancer and 18% risk for ovarian cancer (3). However, the risks may vary depending on family history or other modifying risk alleles (4, 5). The proteins encoded by these genes have an essential role in the maintenance of genomic integrity by homologous recombination repair of DNA double-strand breaks. They carry out these functions through interactions with a diverse network of other proteins (6). One of the most important interaction partners for BRCA2 is PALB2.PALB2 (partner and localizer for BRCA2) has an important function in the regulation and localization of BRCA2 (7). PALB2 protein colocalizes with BRCA2 in nuclear foci, strongly increasing the stability of BRCA2. PALB2 p...

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Section: Discussionsupporting

confidence: 54%

The Breast Cancer Susceptibility Mutation PALB2 1592delT Is Associated with an Aggressive Tumor Phenotype

Heikkinen

Kärkkäinen

Aaltonen

et al. 2009

Clinical Cancer Research

124

103

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“…[90][91][92][93][94] This may be in part due to the presence of a dysfunctional BRCA1 pathway in these tumors. 32,82,83 BRCA1 gene promoter is methylated in 460% of medullary 95,96 and metaplastic 32 breast cancers of basal-like phenotype.…”

Section: S Badve Et Almentioning

confidence: 99%

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

et al. 2011

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Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

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“…S1), with p53 mutations, and with the basal-like phenotype (Fig. S2), a class of breast cancer that has greater chromosomal copy number variation and genetic complexity than other subtypes of breast cancer (19)(20)(21).…”

Section: High Levels Of Mps1 Correlate With High Histologic Grade In mentioning

confidence: 99%

High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells

Daniel

Coulter

Woo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

141

144

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Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 contribute to the ability of breast cancer cells to tolerate this aneuploidy. Reducing Mps1 levels in cultured human breast cancer cells by RNAi resulted in aberrant mitoses, induction of apoptosis, and decreased ability of human breast cancer cells to grow as xenografts in nude mice. Remarkably, breast cancer cells that survive reductions in levels of Mps1 have relatively less aneuploidy, as measured by copies of specific chromosomes, compared with cells that have constitutively high levels of Mps1. Thus, high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy.

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

Cited by 72 publications

References 41 publications

The Breast Cancer Susceptibility Mutation PALB2 1592delT Is Associated with an Aggressive Tumor Phenotype

The Breast Cancer Susceptibility Mutation PALB2 1592delT Is Associated with an Aggressive Tumor Phenotype

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells

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