scholarly journals Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a breast cancer susceptibility locus at 12q15

2017 ◽  
Author(s):  
Michael J Madsen ◽  
Stacey Knight ◽  
Carol Sweeney ◽  
Rachel Factor ◽  
Mohamed Salama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Expression Patterns ◽  
Breast Tumors ◽  
Two Dimensions ◽  
Three Dimensions ◽  
Tumor Characteristics ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B

AbstractIt is well-known that breast tumors exhibit different expression patterns that can be used to assign intrinsic subtypes – the PAM50 assay, for example, categorizes tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like – yet tumors are often more complex than categorization can describe. We used 911 sporadic breast tumors to reparameterize expression from the PAM50 genes to five orthogonal tumor dimensions using principal components (PC). Three dimensions captured intrinsic subtype, two dimensions were novel, and all replicated in 945 TCGA tumors. By definition dimensions are independent, an important attribute for inclusion in downstream studies exploring effects of tumor diversity. One application where tumor subtyping has failed to provide impact is susceptibility genetics. Germline genetic heterogeneity reduces power for gene-finding. The identification of heritable tumor characteristics has potential to increase homogeneity. We compared 238 breast tumors from high-risk pedigrees not attributable to BRCA1 or BRCA2 to 911 sporadic breast tumors. Two PC dimensions were significantly enriched in the pedigrees (intrinsic subtypes were not). We performed proof-of-concept gene-mapping in one enriched pedigree and identified a 0.5 Mb genomewide significant region at 12q15 that segregated to the 8 breast cancer cases with the most extreme PC tumors through 32 meioses (p=2.6×10−8). In conclusion, our study: suggests a new approach to describe tumor diversity; supports the hypothesis that tumor characteristics are heritable providing new avenues for germline studies; and proposes a new breast cancer locus. Reparameterization of expression patterns may similarly inform other studies attempting to model the effects of tumor heterogeneity.

scholarly journals Re-definition of claudin-low as a breast cancer phenotype

2019 ◽  
Author(s):  
Christian Fougner ◽  
Helga Bergholtz ◽  
Jens Henrik Norum ◽  
Therese Sørlie
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Breast Tumors ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Diverse Range ◽  
Luminal B ◽  
Cancer Phenotype ◽  
Definition Of

The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors were distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflected characteristics of their intrinsic subtype. Finally, we have developed an alternative method for identifying claudin-low tumors and thereby uncovered potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.Contact informationC.F. [email protected]. [email protected]. [email protected]. [email protected]

scholarly journals Heterogeneity of Breast Cancer Associations with Common Genetic Variants inFGFR2according to the Intrinsic Subtypes in Southern Han Chinese Women

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huiying Liang ◽  
Xuexi Yang ◽  
Lujia Chen ◽  
Hong Li ◽  
Anna Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Chinese Women ◽  
Intrinsic Subtype ◽  
Han Chinese ◽  
Dependent Manner ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B ◽  
Common Genetic Variants

GWAS have identified variation in theFGFR2locus as risk factors for breast cancer. Validation studies, however, have shown inconsistent results by ethnics and pathological characteristics. To further explore this inconsistency and investigate the associations ofFGFR2variants with breast cancer according to intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative) among Southern Han Chinese women, we genotyped rs1078806, rs1219648, rs2420946, rs2981579, and rs2981582 polymorphisms in 609 patients and 882 controls. Significant associations with breast cancer risk were observed for rs2420946, rs2981579, and rs2981582 with OR (95% CI) per risk allele of 1.19 (1.03–1.39), 1.24 (1.07–1.43), and 1.17 (1.01–1.36), respectively. In subtype specific analysis, above three SNPs were significantly associated with increased Luminal-A risk in a dose-dependent mannerPtrend<0.01; however, only rs2981579 was associated with Luminal-B, and none were linked to ER−&PR− subtypes (ER−&PR−&HER2+ and triple negative). Haplotype analyses also identified common haplotypes significantly associated with luminal-like subtypes (Luminal-A and Luminal-B), but not with ER−&PR− subtypes. Our results suggest that associations ofFGFR2SNPs with breast cancer were heterogeneous according to intrinsic subtype. Future studies stratifying patients by their intrinsic subtypes will provide new insights into the complex genetic mechanisms underlying breast cancer.

Pathological response and its effect on survival with neoadjuvant chemotherapy according to intrinsic subtype in locally advanced breast cancers in north India: Is it different from the West?

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 90-90
Author(s):  
Sushma Agrawal ◽  
Punita Lal ◽  
Shaleen Kumar ◽  
Gaurav Agarwal ◽  
Anjali Mishra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Pathological Response ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B ◽  
Basal Subtype ◽  
Her 2

90 Background: Breast cancer patients commonly present in locally advanced stage (LABC) in our country. We propose to correlate the pathological response to neoadjuvant chemotherapy (NACT) and its impact on survival based on the intrinsic subtypes. Methods: Consecutive patients of LABC who underwent NACT (taxane and or anthracyclines based )followed by definitive surgery and radiotherapy during the period January 2007 to December 2012 were grouped on the basis of intrinsic subtypes (Luminal A, Luminal B, Her-2 Type, Basal). The pathological response to NACT in tumour as well as axillary nodes [complete response (pCR), partial response (pPR)] was correlated with the disease free survival (DFS) and overall survival (OS) at 5 years in the intrinsic subtypes using Kaplan Meier Analysis. Results: Among 208 patients the median age was 46 years (range 24-81 years), 46% premenopausal,54% postmenopausal, presenting tumour and node stage was 15% T2, 40% T3, 45% T4,8% N0, 42% N1, 41% N2, 9% N3.The intrinsic subtypes at presentation were Luminal A (16%), Luminal B (23%), Her-2 Type (23%), Basal (37%).The pCR rate in node was significantly higher in Her-2 type and Basal subtype (Table ). At a median followup of 34 months (range 6-84 mo)the 5 year DFS and OS was significantly higher in patients achieving pCR tumour or node in Her-2 type and Basal subtype (Table ). Conclusions: The pCR rate to NACT in tumour or node seems to be considerably higher in our population than that reported in the western literature. pCR (tumour and node) is a surrogate for both DFS and OS at 5 years in Her-2 and basal subtypes of breast cancer. [Table: see text]

scholarly journals Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Cindy K. Blair ◽  
Charles L. Wiggins ◽  
Andrea M. Nibbe ◽  
Curt B. Storlie ◽  
Eric R. Prossnitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Tumor Characteristics ◽  
Obese Women ◽  
Luminal A ◽  
Luminal B ◽  
Breast Cancer Specific Mortality ◽  
Specific Mortality ◽  
Cancer Specific Mortality

Abstract Obesity exerts adverse effects on breast cancer survival, but the means have not been fully elucidated. We evaluated obesity as a contributor to breast cancer survival according to tumor molecular subtypes in a population-based case–cohort study using data from the Surveillance Epidemiology and End Results (SEER) program. We determined whether obese women were more likely to be diagnosed with poor prognosis tumor characteristics and quantified the contribution of obesity to survival. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated via Cox multivariate models. The effect of obesity on survival was evaluated among 859 incident breast cancers (subcohort; 15% random sample; median survival 7.8 years) and 697 deaths from breast cancer (cases; 100% sample). Obese women had a 1.7- and 1.8-fold increased risk of stage III/IV disease and grade 3/4 tumors, respectively. Obese women with Luminal A- and Luminal B-like breast cancer were 1.8 (95% CI 1.3–2.5) and 2.2 (95% CI 0.9–5.0) times more likely to die from their cancer compared to normal weight women. In mediation analyses, the proportion of excess mortality attributable to tumor characteristics was 36.1% overall and 41% and 38% for Luminal A- and Luminal B-like disease, respectively. Obesity was not associated with breast cancer-specific mortality among women who had Her2-overexpressing or triple-negative tumors. Obesity may influence hormone-positive breast cancer-specific mortality in part through fostering poor prognosis tumors. When tumor biology is considered as part of the causal pathway, the public health impact of obesity on breast cancer survival may be greater than previously estimated.

scholarly journals Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 507 ◽  
Author(s):  
Shujun Huang ◽  
Wayne Xu ◽  
Pingzhao Hu ◽  
Ted M. Lakowski
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Binding Sites ◽  
Triple Negative ◽  
Expression Patterns ◽  
Lasso Regression ◽  
Luminal A ◽  
Luminal B ◽  
Number Variation ◽  
Yin And Yang

Different breast cancer (BC) subtypes have unique gene expression patterns, but their regulatory mechanisms have yet to be fully elucidated. We hypothesized that the top upregulated (Yin) and downregulated (Yang) genes determine the fate of cancer cells. To reveal the regulatory determinants of these Yin and Yang genes in different BC subtypes, we developed a lasso regression model integrating DNA methylation (DM), copy number variation (CNV) and microRNA (miRNA) expression of 391 BC patients, coupled with miRNA–target interactions and transcription factor (TF) binding sites. A total of 25, 20, 15 and 24 key regulators were identified for luminal A, luminal B, Her2-enriched, and triple negative (TN) subtypes, respectively. Many of the 24 TN regulators were found to regulate the PPARA and FOXM1 pathways. The Yin Yang gene expression mean ratio (YMR) and combined risk score (CRS) signatures built with either the targets of or the TN regulators were associated with the BC patients’ survival. Previously, we identified FOXM1 and PPARA as the top Yin and Yang pathways in TN, respectively. These two pathways and their regulators could be further explored experimentally, which might help to identify potential therapeutic targets for TN.

scholarly journals Clinical Features and Survival of Pregnancy-Associated Breast Cancer: A Retrospective Study of 203 Cases in China

2020 ◽  
Author(s):  
Bo-yue Han ◽  
Xiao-guang Li ◽  
Hai-yun Zhao ◽  
Xin Hu ◽  
Hong Ling
Keyword(s):  
Breast Cancer ◽  
Pregnant Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Cancer Center ◽  
Tumor Characteristics ◽  
Luminal A ◽  
Luminal B ◽  
Her 2

Abstract Purpose: Pregnancy-associated breast cancer (PABC) is an aggressive disease, and sinceChinese authoritybegan to encourage childbearing in 2015, the incidence of PABC has increased. This study investigated the characteristics and survival of PABC patients. Methods: Patients with PABC who underwent surgery at Fudan University, Shanghai Cancer Center between 2005 and 2018 were enrolled.Data concerning the tumor characteristics, maternal state (whether first or non-first pregnancy ) and survival outcome were recorded. Pearson Chi-square tests were used to compare the characteristics of the tumors, and Kaplan-Meier methods were used to perform the survival analysis. Results: Overall, 203 PABC patients were recruited. Since 2015, 65.5% of non-first pregnant women were diagnosed with breast cancer, it’s 5.7 fold of the incidence of PABC in non-first pregnant women. No significant differences in tumor characteristics were observed between the patients who were in their first pregnancy and those in non-first pregnancy. Among the entire PABC population, luminal B breast cancer accounted for the largest proportion (38.4%), followed by triple-negative breast cancer (TNBC, 30.0%). The distribution of the molecular subtypes of PABC and non-PABC differed (P<0.001) as follows: in the PABC patients, Luminal B 38.4%, Triple negative breast cancer (TNBC) 30.1%, Human Epidermal Growth Factor Receptor 2 (HER-2) overexpression 15.8%, and Luminal A 10.8%; in the non-PABC patients, Luminal A 50.9%, Luminal B 20.1%, TNBC 17.4%, and HER-2 overexpression 8.0%. The 3-year disease free survival (DFS) of all PABC patients was 80.3%. The 3-year DFS of the patients in the first-pregnancy group was 78.4%, and that of the patients in the non-first-pregnancy group was 83.7% (P=0.325). Conclusions: Our study proved that the proportion of women who developed PABC during the second or third pregnancy was extremely high relative to the newborn populations. The patients in the PABC population tended to present more luminal B and TNBC breast cancer than the non-PABC patients.

Breast cancer intrinsic subtypes by PAM50 in older women.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1524-1524
Author(s):  
Emily Oldham Jenkins ◽  
Allison Mary Deal ◽  
Carey K. Anders ◽  
Aleix Prat ◽  
Charles M. Perou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Biology ◽  
Continuous Variable ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Prognostic Information ◽  
Luminal B ◽  
Kaplan Meier ◽  
Treatment Data

1524 Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p<0.01, p<0.0001, p<0.0001, respectively), while the percentage of basal tumors decreased (p<0.0001). Basal tumors represented 13% of pts aged > 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p<0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]

scholarly journals Germline breast cancer susceptibility genes, tumor characteristics, and survival

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Peh Joo Ho ◽  
Alexis J. Khng ◽  
Hui Wen Loh ◽  
Weang-Kee Ho ◽  
Cheng Har Yip ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Tumor Characteristics ◽  
Breast Cancer Patients ◽  
Luminal B ◽  
Cancer Susceptibility Genes

Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

scholarly journals Gene Co-Expression in Breast Cancer: A Matter of Distance

2021 ◽  
Vol 11 ◽  
Author(s):  
Alfredo González-Espinoza ◽  
Jose Zamora-Fuentes ◽  
Enrique Hernández-Lemus ◽  
Jesús Espinal-Enríquez
Keyword(s):  
Breast Cancer ◽  
Pearson Correlation ◽  
Expression Patterns ◽  
Null Model ◽  
Gene Clusters ◽  
Chromosome Location ◽  
Luminal A ◽  
Long Distance ◽  
Cancer Subtypes ◽  
Luminal B

Gene regulatory and signaling phenomena are known to be relevant players underlying the establishment of cellular phenotypes. It is also known that such regulatory programs are disrupted in cancer, leading to the onset and development of malignant phenotypes. Gene co-expression matrices have allowed us to compare and analyze complex phenotypes such as breast cancer (BrCa) and their control counterparts. Global co-expression patterns have revealed, for instance, that the highest gene-gene co-expression interactions often occur between genes from the same chromosome (cis-), meanwhile inter-chromosome (trans-) interactions are scarce and have lower correlation values. Furthermore, strength of cis- correlations have been shown to decay with the chromosome distance of gene couples. Despite this loss of long-distance co-expression has been clearly identified, it has been observed only in a small fraction of the whole co-expression landscape, namely the most significant interactions. For that reason, an approach that takes into account the whole interaction set results appealing. In this work, we developed a hybrid method to analyze whole-chromosome Pearson correlation matrices for the four BrCa subtypes (Luminal A, Luminal B, HER2+ and Basal), as well as adjacent normal breast tissue derived matrices. We implemented a systematic method for clustering gene couples, by using eigenvalue spectral decomposition and the k–medoids algorithm, allowing us to determine a number of clusters without removing any interaction. With this method we compared, for each chromosome in the five phenotypes: a) Whether or not the gene-gene co-expression decays with the distance in the breast cancer subtypes b) the chromosome location of cis- clusters of gene couples, and c) whether or not the loss of long-distance co-expression is observed in the whole range of interactions. We found that in the correlation matrix for the control phenotype, positive and negative Pearson correlations deviate from a random null model independently of the distance between couples. Conversely, for all BrCa subtypes, in all chromosomes, positive correlations decay with distance, and negative correlations do not differ from the null model. We also found that BrCa clusters are distance-dependent, meanwhile for the control phenotype, chromosome location does not determine the clustering. To our knowledge, this is the first time that a dependence on distance is reported for gene clusters in breast cancer. Since this method uses the whole cis- interaction geneset, combination with other -omics approaches may provide further evidence to understand in a more integrative fashion, the mechanisms that disrupt gene regulation in cancer.

scholarly journals Clinical Features and Survival of Pregnancy-Associated Breast Cancer: A Retrospective Study of 203 Cases in China

2020 ◽  
Author(s):  
Bo-yue Han ◽  
Xiao-guang Li ◽  
Hai-yun Zhao ◽  
Xin Hu ◽  
Hong Ling
Keyword(s):  
Breast Cancer ◽  
Pregnant Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Cancer Center ◽  
Tumor Characteristics ◽  
Luminal A ◽  
Luminal B ◽  
Her 2

Abstract Background: Pregnancy-associated breast cancer (PABC) is an aggressive disease, and sinceChinese authoritybegan to encourage childbearing in 2015, the incidence of PABC has increased. This study investigated the characteristics and survival of PABC patients. Methods: Patients with PABC who underwent surgery at Fudan University, Shanghai Cancer Center between 2005 and 2018 were enrolled.Data concerning the tumor characteristics, maternal state (whether first or non-first pregnancy ) and survival outcome were recorded. Pearson Chi-square tests were used to compare the characteristics of the tumors, and Kaplan-Meier methods were used to perform the survival analysis. Results: Overall, 203 PABC patients were recruited. Since 2015, 65.5% of non-first pregnant women were diagnosed with breast cancer, it’s 5.7 fold of the incidence of PABC in non-first pregnant women. No significant differences in tumor characteristics were observed between the patients who were in their first pregnancy and those in non-first pregnancy. Among the entire PABC population, luminal B breast cancer accounted for the largest proportion (38.4%), followed by triple-negative breast cancer (TNBC, 30.0%). The distribution of the molecular subtypes of PABC and non-PABC differed (P<0.001) as follows: in the PABC patients, Luminal B 38.4%, Triple negative breast cancer (TNBC) 30.1%, Human Epidermal Growth Factor Receptor 2 (HER-2) overexpression 15.8%, and Luminal A 10.8%; in the non-PABC patients, Luminal A 50.9%, Luminal B 20.1%, TNBC 17.4%, and HER-2 overexpression 8.0%. The 3-year disease free survival (DFS) of all PABC patients was 80.3%. The 3-year DFS of the patients in the first-pregnancy group was 78.4%, and that of the patients in the non-first-pregnancy group was 83.7% (P=0.325). Conclusions: Our study proved that the proportion of women who developed PABC during the second or third pregnancy was extremely high relative to the newborn populations. The patients in the PABC population tended to present more luminal B and TNBC breast cancer than the non-PABC patients.

Sign in / Sign up

Export Citation Format

Share Document