scholarly journals High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

2021 ◽  
pp. jmedgenet-2020-107347
Author(s):  
D Gareth Evans ◽  
Elke Maria van Veen ◽  
Helen J Byers ◽  
Sarah J Evans ◽  
George J Burghel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
Ductal Carcinoma ◽  
Cancer Genes ◽  
Early Onset Breast Cancer ◽  
Younger Women ◽  
Pathogenic Variants ◽  
Younger Age ◽  
Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Somatic and germline mutation profiles of Chinese breast cancer patients younger than 35.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 554-554
Author(s):  
Ning Liao ◽  
Guo-Chun Zhang ◽  
Xiaoqing Chen ◽  
Weikai Xiao ◽  
Jianguo Lai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Germline Mutation ◽  
Early Onset ◽  
Chinese Women ◽  
Germline Mutations ◽  
Breast Cancer Patients ◽  
Early Onset Breast Cancer ◽  
Younger Women

554 Background: Limited studies have investigated the molecular underpinnings driving breast cancer development in Chinese younger women. Based from our previous data, more Chinese women are diagnosed with early-onset breast cancer than in the West. In our study, we aim to investigate the comprehensive mutational profile of Chinese women 35 years old and younger (≤35y) diagnosed with breast cancer. Methods: Targeted sequencing was performed on surgically-removed tumor tissues and blood samples collected from 589 women diagnosed with stage I-III breast cancer of various molecular subtypes at the Guangdong Provincial People’s Hospital (GPDH) using a gene panel interrogating 520 cancer-related genes. We compared the data of 53 women aged ≤35y from our cohort to the data from 33 breast cancer patients aged ≤35y included in The Cancer Genome Atlas (TCGA) dataset. Results: Among the women aged ≤35y with early-stage breast cancer from both cohorts, our cohort had more number of hormone receptor-positive (HR+) patients (GPDH, 72% vs. TCGA, 61%, P< 0.001). Analysis revealed an overall mutation detection rate of 98% in our cohort, with mutations affecting genes involved in the PI3K pathway (47%) and cell cycle pathway (23%). TP53 and PIK3CA were the most commonly mutated genes, with mutation rates of 51% and 25% from our cohort. No statistical difference in mutation profile was found between GPDH and TCGA cohorts. Moreover, germline mutations considered as pathogenic and likely pathogenic (P/LP) in breast cancer susceptibility genes including BRCA1 (n = 4), BRCA2 (n = 2), PALB2 (n = 1), PMS2 (n = 1), PTEN (n = 1), and ATM (n = 1) were detected from 18.9% (10/53) of the patients from our cohort. Women aged ≤35y had significantly more germline BRCA1 mutations than patients > 35y from our cohort (7.5%, 4/53 vs. 2.1%, 11/536 P= 0.049). Conclusions: Our study has identified the involvement of PI3K and cell cycle as the two key pathways in the early development of breast tumors in younger women. In addition, our results also support the role of P/LP germline mutations in breast oncogenesis in Chinese patients with early-onset breast cancer, indicating the need to include a more comprehensive germline mutation screening in our population.

Mutational analysis of key genes in patients from the Kazakh population with early onset of breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13038-e13038
Author(s):  
Dilyara Kaidarova ◽  
Nazgul Omarbayeva ◽  
Gulnur Zhunussova ◽  
Aliya Abdrakhmanova ◽  
Saltanat Abdikerim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
Mutational Analysis ◽  
Reproductive Age ◽  
Missense Mutations ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Key Genes ◽  
Clinically Significant ◽  
Brca1 Brca2

e13038 Background: Breast cancer (BC) represents the most common malignancy and has the highest mortality among women, both in the world and in Kazakhstan. Approximately 20-30% of cases of hereditary BC are caused by presence of BRCA1/2 genes defects. Also, there are additional genes which can increase the risk of BC and they are still under study.The aim of this study was to identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) of young BC patients. Methods: Blood was collected from 129 BC patients (average age 34.87±5.587). DNAs were extracted using GeneJET Genomic DNA Purification Kit. NGS was done on the MiSeq platform using TruSightCancer Kit. NGS data were analyzed by the MiSeq Reporter v. 2.4 software. Variant annotation and interpretation was done by Variant Studio 3.0 software. Results: We perform the NGS and did the detailed bioinformatics analysis of sequences of 16 key genes of BC (BRCA1/BRCA2, BRIP1, ATM, CDH1, CHEK2, NBN, NF1, PALB2, STK11, TP53, RAD51C, RAD51D, BARD1, MUTYH and FANCC). At all 3016 variants were detected, 1080 (35.8%) out of which were missense; 1494 (49.5%) synonymous; 17 (0.6%) frameshifts; 2 (0.06%) inframe deletions, 8 (0.3%) stop gained; 4 (0.1%) splice variant, 411 (13.6%) intron or non-coding variants. We identified 24 pathogenic and likely pathogenic mutations in 31 patients (24% of all patient cohort), 3 mutations are novel. All mutations were in heterozygous state and were rare or had frequency data not available (NA) in 1000G, ESP6500and ExAC databases. Analysis of mutation type revealed 17 frameshift mutations, 2 missense mutations, 8 stop gained mutations, 4 mutations involving uncorrected splicing. Out of the 31 pathogenic and likely pathogenic variants, were detected 14 in BRCA1, 9 in BRCA2, 4 in TP53 genes, 3 in PALB2 and 1 in NBN. (BRCA2: c.6468_6469delTC, c.7567_7568delCT, c.9976A > T, c.8174G > A, c.2442delC, c.2808_2811delACAA, c.9253delA, c.9409dupA and c.6058G > T; BRCA1: c.2498delT, c.5224C > T, c.3020C > G, c.3352C > T, c.5530+1G > A, c.5341-2delA and BRCA1-c.5329dupC in 6 cases; NBN: c.657_661delACAAA; PALB2: c.172_175delTTGT, c.1034T > G and c.18_22delGAAGC; TP53- c.156dupA, c.1024C > T, c.844C > T and c.584T > C). The most frequent genes were BRCA1 (45%) and BRCA2 (29%). Conclusions: The study focused on identifying mutation profile of early onset BC using NGS. Clinically significant variants was detected which are promising biomarkers for the successful diagnosis and therapy of BC at women in reproductive age.

scholarly journals Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry

PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0165436 ◽  
Author(s):  
Cameron M. Scott ◽  
JiHoon Eric Joo ◽  
Neil O’Callaghan ◽  
Daniel D. Buchanan ◽  
Mark Clendenning ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
Cancer Predisposition ◽  
Early Onset Breast Cancer ◽  
Breast Cancer Family ◽  
Cancer Family ◽  
Breast Cancer Predisposition ◽  
Predisposition Genes

scholarly journals Genetic testing in women with early-onset breast cancer: a Traceback pilot study

2021 ◽  
Author(s):  
Annelie Augustinsson ◽  
Martin P. Nilsson ◽  
Carolina Ellberg ◽  
Ulf Kristoffersson ◽  
Håkan Olsson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Counseling ◽  
Genetic Testing ◽  
Pilot Study ◽  
Early Onset ◽  
Early Onset Breast Cancer ◽  
Clinical Implementation ◽  
Test Information ◽  
Pathogenic Variants ◽  
Post Test

Abstract Purpose In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. Methods Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. Results Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. Conclusion The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Comparison of Mammography and Ultrasonography for Tumor Size of DCIS of Breast Cancer

2019 ◽  
Vol 15 (2) ◽  
pp. 209-213
Author(s):  
Yu Wang ◽  
Jiantao Wang ◽  
Haiping Wang ◽  
Xinyu Yang ◽  
Liming Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Correlation Coefficient ◽  
Tumor Size ◽  
Ductal Carcinoma ◽  
Pearson Correlation ◽  
Dense Breast ◽  
Pathological Examination ◽  
Negative Group ◽  
The Difference

Objective: Accurate assessment of breast tumor size preoperatively is important for the initial decision-making in surgical approach. Therefore, we aimed to compare efficacy of mammography and ultrasonography in ductal carcinoma in situ (DCIS) of breast cancer. Methods: Preoperative mammography and ultrasonography were performed on 104 women with DCIS of breast cancer. We compared the accuracy of each of the imaging modalities with pathological size by Pearson correlation. For each modality, it was considered concordant if the difference between imaging assessment and pathological measurement is less than 0.5cm. Results: At pathological examination tumor size ranged from 0.4cm to 7.2cm in largest diameter. For mammographically determined size versus pathological size, correlation coefficient of r was 0.786 and for ultrasonography it was 0.651. Grouped by breast composition, in almost entirely fatty and scattered areas of fibroglandular dense breast, correlation coefficient of r was 0.790 for mammography and 0.678 for ultrasonography; in heterogeneously dense and extremely dense breast, correlation coefficient of r was 0.770 for mammography and 0.548 for ultrasonography. In microcalcification positive group, coeffient of r was 0.772 for mammography and 0.570 for ultrasonography. In microcalcification negative group, coeffient of r was 0.806 for mammography and 0.783 for ultrasonography. Conclusion: Mammography was more accurate than ultrasonography in measuring the largest cancer diameter in DCIS of breast cancer. The correlation coefficient improved in the group of almost entirely fatty/ scattered areas of fibroglandular dense breast or in microcalcification negative group.

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