scholarly journals ­­Differences in somatic TP53 Mutation Type in Breast Tumors by Race and Receptor Status

2021 ◽  
Author(s):  
Nijole C Pollock ◽  
Johnny R Ramroop ◽  
Heather Hampel ◽  
Melissa A Troester ◽  
Kathleen Conway ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tp53 Mutation ◽  
Cpg Island ◽  
African Ancestry ◽  
Breast Tumors ◽  
Dominant Negative ◽  
Driver Mutations ◽  
Loss Of Function ◽  
Receptor Status ◽  
Mutation Type

Abstract Background: Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. Breast cancers arising in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than non-Hispanic White (NHW) women. Missense driver mutations in TP53 are known to have different functional effects including loss-of function (LOF) or gain-of-function (GOF) activity. A subset of variants exhibit dominant negative (DNE) activity over wildtype TP53 or other TP53 family members. Methods: To determine if there were differences in TP53 mutation type by race or TNBC status we identified published and unpublished datasets with somatic mutation data, race, age, and hormone receptor status. Mutations were classified as LOF, GOF or CpG Island hotspot by published literature or type of mutation (e.g. frameshift and nonsense mutations were considered to be LOF). We used Fisher’s Exact test to assess for significant differences.Results: We identified 96 independent breast cancer studies with race and somatic TP53 mutation status available. The study comprised data from a total of 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. Of the total TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, and the remaining 286 (9.6%) were not able to be classified. With respect to DNE activity, 1246 (42%) showed activity, 1190 (40.1%) showed no activity, and 528 (17.8%) were unknown status. The distribution of TP53 mutation type was similar by race and ethnicity. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations lacking DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and estrogen receptor (ER) negative status (OR=1.38; p=0.005). Conclusions: In summary, ER negative and TNBC breast tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts are needed to further elucidate some of these findings.

scholarly journals ­­Differences in Somatic TP53 Mutation Type in Breast Tumors by Race and Receptor Status

2021 ◽  
Author(s):  
Nijole C Pollock ◽  
Johnny Ramroop ◽  
Heather Hampel ◽  
Melissa A. Troester ◽  
Kathleen Conway ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tp53 Mutation ◽  
African Ancestry ◽  
Dominant Negative ◽  
Driver Mutations ◽  
Published Data ◽  
Functional Impact ◽  
Receptor Status ◽  
Tp53 Mutations ◽  
Mutation Type

Abstract Purpose: Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status. Methods: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher’s exact test. Results: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p=0.04). Mutations with DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and estrogen receptor (ER) negative status (OR=1.38; p=0.005).Conclusions: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings.

Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers

2015 ◽  
Vol 33 (21) ◽  
pp. 2345-2352 ◽  
Author(s):  
Gaëlle Bougeard ◽  
Mariette Renaux-Petel ◽  
Jean-Michel Flaman ◽  
Camille Charbonnier ◽  
Pierre Fermey ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Soft Tissue Sarcomas ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Li Fraumeni Syndrome ◽  
Tumor Onset ◽  
Mutation Carriers ◽  
The Mean ◽  
Li Fraumeni

Purpose The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

scholarly journals P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Jonathan D. Marotti ◽  
Kristen E. Muller ◽  
Laura J. Tafe ◽  
Eugene Demidenko ◽  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Tumors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Solid Organ ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Receptor Status ◽  
Cancer Subtypes

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.

Abnormal demethylation and ectopic expression of leukotriene receptors genes LTB4R/LTB4R2 in breast cancer

2021 ◽  
pp. 21-30
Author(s):  
А.И. Калинкин ◽  
В.О. Сигин ◽  
М.В. Немцова ◽  
Е.Б. Кузнецова ◽  
Т.В. Кекеева ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Bisulfite Sequencing ◽  
Cpg Island ◽  
Breast Tumors ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome ◽  
Leukotriene Receptor

Введение. Выявление и всесторонняя характеристика новых молекулярных маркеров злокачественных опухолей остаётся актуальной задачей онкологии. Ранее по результатам проведенного авторами широкогеномного скрининга дифференциального метилирования ДНК нормальных и опухолевых тканей молочной железы (МЖ) было выявлено аномальное деметилирование CpG-островка генов LTB4R/LTB4R2 в опухолях относительно нормы. Цель. Настоящее исследование посвящено молекулярной и клинической характеристике аномального деметилирования этого CpG-островка и экспрессии генов LTB4R/LTB4R2 при раке молочной железы (РМЖ). Методы. Для разведочного анализа использовали полученные авторами ранее результаты широкогеномного бисульфитного секвенирования Xmal-RRBS 110 образцов РМЖ и 6 образцов нормальной МЖ. В этой выборке был проведен сравнительный анализ уровней метилирования CpG-динуклеотидов в нормальной и опухолевой ткани 10 образцов трижды негативного (ТН) РМЖ с аномальным деметилированием LTB4R/LTB4R2 и 6 образцов нормальной МЖ с использованием критерия Манна-Уитни. Для подтверждения аномального деметилирования в образцах ТН РМЖ было использовано бисульфитное секвенирование по Сэнгеру. Для изучения корреляции между уровнями метилирования и экспрессии и для оценки прогностической значимости экспрессии генов LTB4R/LTB4R2 использовали данные 3 уровня по измерению метилирования с чипов Illumina HumanMethylation 450K, экспрессии RNA-seq, а также клинические характеристики 731 образцов из проекта TCGA-BRCA. Отличия между кривыми Каплана-Мейера сравнивали с использованием логранкового критерия. Результаты. Определено, что аномальное деметилирование CpG-островка генов LTB4R/LTB4R2 характерно для эпигеномного подтипа умеренно метилированных образцов ТН РМЖ. Определены дифференциально метилированные CpG-динуклеотиды CpG-островка генов LTB4R/LTB4R2; их дифференциальное метилирование подтверждено бисульфитным секвенированием по Сэнгеру. Установлена отрицательная корреляция между уровнем их метилирования и экспрессией генов LTB4R и LTB4R2. Показано, что общая выживаемость достоверно снижена в группе ТН РМЖ с высокой экспрессией LTB4R, а также в группе нормально-подобных опухолей МЖ с низкой экспрессией LTB4R и в группе LumB опухолей МЖ с низкой экспрессией LTB4R2. Различия показателей выживаемости позволяют рассматривать уровни экспрессии LTB4R/LTB4R2 как прогностический маркер при РМЖ, однако следует учитывать, что прогноз зависит от молекулярного подтипа опухоли. Это относится также к использованию уровней экспрессии LTB4R/LTB4R2 в качестве потенциального предиктивного маркера чувствительности таких опухолей к ингибиторам лейкотриеновых рецепторов при проведении клинических испытаний. Background. The identification and comprehensive characterization of new molecular markers of malignant tumors remains an urgent task of oncology. Earlier, according to the results of a genome-wide screening of differential DNA methylation of normal and tumor breast tissues, abnormal demethylation of the CpG island of LTB4R/LTB4R2 genes in tumors relative to norm was revealed. Aim. The present study focuses on the molecular and clinical characterization of abnormal demethylation of this CpG island and expression of the LTB4R/LTB4R2 genes in breast cancer (BC). Methods. For exploratory analysis, we used the previously obtained results of genome wide bisulfite sequencing of breast cancer (BC) and normal mammary gland samples. From this set, 10 samples of triple-negative (TN) breast cancer with abnormal LTB4R/LTB4R2 demethylation and 6 normal breast samples were selected, for which a comparative analysis of CpG methylation levels in cancer vs norm using the Mann-Whitney test was performed. Sanger bisulfite sequencing was used to confirm abnormal demethylation in TN BC samples. The analysis of the obtained electrophoregrams was carried out using the SeqBase software developed by the authors. To validate and assess the level of predictive significance of LTB4R/LTB4R2 gene expression, level 3 data were used to measure methylation from Illumina HumanMethylation 450K arrays, RNA-seq expression, as well as clinical characteristics for 731 samples from the TCGA-BRCA project. Kaplan-Meier curves were compared using a logrank test. Results. Abnormal demethylation of LTB4R/LTB4R2 genes in breast tumors was confirmed by Sanger sequencing. Among samples from the TCGA-BRCA project, a group of TN BC samples with low methylation of LTB4R/LTB4R2 genes was identified. Overall survival was significantly reduced in the TN breast cancer group with high LTB4R expression, as well as in the group of normal-like breast tumors with low LTB4R expression, and in the LumB group overall survival was significantly reduced when tumors demonstrated low LTB4R2 expression. Conclusions. Fine mapping of abnormal demethylation in individual CpG dinucleotides of the LTB4R/LTB4R2 genes will make it possible to design an effective PCR system that may potentially be used to define patients with TN breast cancer that would benefit from leukotriene receptor therapeutic inhibition. Different expression levels of LTB4R/LTB4R2 allow their use as a prognostic marker for breast cancer, but the prognosis directly depends on the molecular subtype of a tumor. This also applies to the use of different levels of LTB4R/LTB4R2 expression as a predictive marker of the sensitivity of such tumors to leukotriene receptor inhibitors in case they enter clinical trials.

scholarly journals The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Nomeda Girnius ◽  
Yvonne JK Edwards ◽  
David S Garlick ◽  
Roger J Davis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Tumor Formation ◽  
Driver Mutations ◽  
Tumor Initiation ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Promote Cell Proliferation ◽  
Jnk Signaling Pathway

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as ‘driver’ mutations that promote genome instability and tumor initiation.

scholarly journals Creating Models to Identify New Therapeutic Options for Aggressive African Breast Cancers

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 206s-206s
Author(s):  
E. Jiagge ◽  
J. Bensenhaver ◽  
K. Celina ◽  
M. Hoenerhoff ◽  
R. Gilani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Screening ◽  
White Women ◽  
African Ancestry ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Therapeutic Options ◽  
Stem Cell Marker ◽  
Breast Cancers ◽  
Background Population

Background: Population-based incidence rates of breast cancer (BC) that does not express the estrogen receptor (ER), progesterone receptor (PR) or overexpress the human epidermal growth factor 2 HER2/ neu (triple negative breast cancer, TNBC) are higher among Africans compared with white women. However the underlying biologic and genetic differences among different ethnicities are poorly understood and there are currently very few ethnically diverse BC models available for identifying new therapeutic options. Aim: Establish an international collaboration to: i, characterize African breast tumors ii, create models for studying these tumors and iii, identify biomarkers for early detection and treatment personalization. Methods: We have collected tumors from 154 white Americans WA, 76 African Americans, AA, 190 Ethiopians, Eth, and 286 Ghanaian (Gh) BC patients. We then established a unique resource of patient derived xenografts (PDX) from these tumors. The PDXs were then fully characterized using whole exome and RNA sequencing for the primary tumor, matched normal DNA, and corresponding low passage PDXs. Using immunohistochemistry, we evaluated the ER, PR, HER2/ neu, androgen receptor (AR), and ALDH1 (cancer stem cell marker) expression among these tumors. Based on biomarker expression the PDXs were then tested against a panel of IND drugs, either alone or in combinations, in an ex vivo organoid culture system to discover potential new therapeutic options. Results: Mean age at BC diagnosis was 43; 49; 60; and 57 years for the Eth; Gh; AA; and WA patients, respectively. The proportion of TNBC was significantly higher for the AA and Gh patients (41% and 54%, respectively) compared with the WA and Eth patients (23% and 15%, respectively); P < 0.001. Significant differences were observed for distribution of AR positivity, which was 71%; 55%; 42% and 50% for the WA; AA; Gh; and Eth cases, respectively ( P = 0.008). The Gh breast tumors exhibited the highest number of loss of function and missense mutations that are likely to impact therapy with a high frequency of P53, APC, and FGFR mutations. These mutations were maintained in the corresponding PDXs that were developed, and were thus used as biomarkers for drug screening. These tumors exhibited a gene expression signature based on the ethnicity of the patients with 2385 genes differentially expressed between Gh and AA, 1573 between AA and CA and 1317 between GH and CA. Results from our ongoing drug screening and biomarker identification will be available soon. Conclusions: Establishing the molecular and genetic platform of aggressive breast cancers occurring in women with African ancestry will help in identifying biomarkers for early cancer detection and targeted treatment stratification for optimum patient outcome. The availability of tumor models based on tumors from diverse African populations is the important missing pieces that have to be incorporated into current drug discovery efforts.

scholarly journals Analytic study of hormone receptor status of breast cancer patients visiting in a tertiary care hospital of North-West India

2021 ◽  
Vol 8 (2) ◽  
pp. 612
Author(s):  
Vikas Kakkar ◽  
Arvind Kaushal ◽  
Swaraj Hanspal ◽  
Karanvir Singh ◽  
Anmol Randhawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Progesterone Receptor ◽  
Hormone Receptor ◽  
Older Patients ◽  
Age Groups ◽  
Breast Tumors ◽  
Hormone Receptor Status ◽  
Receptor Status ◽  
Her 2

Background: Increasing evidence shows the importance of young age, estrogen receptor (ER), progesterone receptor (PR) status, and HER-2 expression in patients with breast cancers. Breast tumors in younger age groups were more likely to be of higher grade, hormone receptor– negative, poorly differentiated, and aneuploid, and to have high S-phase fraction, abnormal expression of P53, greater extent of lymphovascular invasion, and over-expression of human epidermal growth factor receptor 2 (HER-2) than breast tumors in older age groups.  Methods: We organised a retrospective study of 600 women diagnosed with breast cancer, who have been operated from 2016 to 2020. We evaluated age, size, hormone receptor status, HER-2 receptor status. Estrogen receptor and progesterone receptor status were evaluated by immunohistochemistry. Results: Total 600 patient data was evaluated in this study. Rate of hormone positivity is more in older patients than in younger patients.  Conclusions: In this study we conclude that the hormone positivity in younger patient is less as compared to older patients.  

Correlation of tumor mutational burden (TMB) with CDKN2A and TP53 mutation in HPV-negative head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6552-6552 ◽  
Author(s):  
Barbara Burtness ◽  
Alexander Deneka ◽  
Yasmine Baca ◽  
Ilya Serebriiskii ◽  
Mitchell I. Parker ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Tp53 Mutation ◽  
Predictive Biomarker ◽  
Dominant Negative ◽  
Alternative Methods ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Tp53 Mutations ◽  
Cdkn2a Mutation ◽  
Mutational Status

6552 Background: The tumor suppressors TP53 and CDKN2A are commonly mutated or lost in HNSCC, impairing G1 checkpoints. This reduces ability to repair DNA damage arising from hypoxia, replication stress, and mutagen exposure, thus increasing TMB, a potential predictive biomarker for immunotherapy benefit. TP53 mutations can be classified as loss-of-function (LOF) with or without dominant negative (DNE) activity, gain-of-function (GOF) and benign. We investigated whether specific categories of TP53 mutation were associated with increased TMB, and whether these cooperated with CDKN2A mutation to elevate TMB. Methods: We analyzed 1010 HPV- HNSCC tumor samples (246 female) profiled with a 592-gene panel by Caris Life Sciences from 2015 to 2019. Predominant subsites were oral cavity (285), oropharynx (225) and larynx (153). TMB reflected all somatic nonsynonymous missense mutations detected. We report mean TMB per megabase (MB). Pathogenicity of TP53 and CDKN2A mutations was determined according to American College of Medical Genetics (ACMG) guidelines. We also used four alternative methods of characterizing TP53 mutations based on analysis of protein structure, public databases (IARC, ClinVar, InterVar), and publications (PMID: 25108461 and others) assessing structure-function relations. Results: 60% of cases had TP53 mutations ( TP53mut) designated pathogenic by ACMG guidelines. Estimates of frequency of LOF/DNE mutations ranged from 30-42.8% of cases among the alternative classification methods. Damaging CDKN2A mutations were present in 20%. Average TMB per MB varied from 8.2/8.6 (females/males) in oral cavity cancers to 26.5/27.7 (females/males) in cancer of the lip. Mean TMB was typically higher in the presence of damaging LOF/DNE TP53 mutations or CDKN2A mutations, but not TP53 GOF mutations. Based on ACMG, for tumors with TP53 and CDKN2A wild type (WT) TMB was 8.03, for those with CDKN2Amut-only 9.82, for TP53mut-only 10.56, and TP53 mut/CDKN2A mut 17.6 (p < 0.001). For disruptive TP53mut (Poeta algorithm), mean TMB for WT/WT was 8.67, for TP53mut 11.31, CDKN2Amut 17.9 and TP53mut/CDKN2A mut 15.83 (p < 0.001). Conclusions: Mutation of TP53 and/or CDKN2A is associated with increased mean TMB relative to WT; mean TMB was highest for tumors bearing damaging mutations in both genes. GOF TP53 mutation was not clearly associated with increased TMB. As TMB is evaluated as a predictive biomarker in the immunotherapy of HNSCC, specific TP53/CDKN2A mutational status should also be evaluated.

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