Early-onset Breast Cancer Patients Research Articles

Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance.

Early-onset breast cancer is known for its aggressive clinical characteristics and high prevalence in East Asian countries, but a comprehensive understanding of its molecular features is still lacking. In this study, we conducted a proteogenomic analysis of 126 treatment-naïve primary tumor tissues obtained from Korean patients with young breast cancer (YBC) aged ≤40 years. By integrating genomic, transcriptomic, and proteomic data, we identified five distinct functional subgroups that accurately represented the clinical characteristics and biological behaviors of patients with YBC. Our integrated approach could be used to determine the proteogenomic status of HER2, enhancing its clinical significance and prognostic value. Furthermore, we present a proteome-based homologous recombination deficiency (HRD) analysis that has the potential to overcome the limitations of conventional genomic HRD tests, facilitating the identification of new patient groups requiring targeted HR deficiency treatments. Additionally, we demonstrated that protein-RNA correlations can be used to predict the late recurrence of hormone receptor-positive breast cancer. Within each molecular subtype of breast cancer, we identified functionally significant protein groups whose differential abundance was closely correlated with the clinical progression of breast cancer. Furthermore, we derived a recurrence predictive index capable of predicting late recurrence, specifically in luminal subtypes, which plays a crucial role in guiding decisions on treatment durations for YBC patients. These findings improve the stratification and clinical implications for patients with YBC by contributing to the optimal adjuvant treatment and duration for favorable clinical outcomes.

Spectrum and characteristics of germline PALB2 pathogenic variants in 1556 early-onset breast cancer patients in China

PurposeLimited data are available regarding the partner and localizer of BRCA2 (PALB2) in Chinese patients with early breast cancer. This study aimed to assess the spectrum and characteristics of germline PALB2 pathogenic variants in this population.MethodsPeripheral blood samples were collected from 1556 patients diagnosed with BRCA1/2-negative early-onset breast cancer. All coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing.ResultsThe prevalence of PALB2 pathogenic variants was approximately 0.77% in the cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations and six nonsense mutations. All other variants were detected once, except for PALB2 c.1056_1057del (detected twice). Two PALB2 carriers (2/12, 16.7%) have documented family history of breast cancer and/or ovarian cancer. Patients with a positive family history exhibited a threefold higher possibility of being identified as PALB2 carriers than those without a family history (2% vs. 0.69%), although the difference was not statistically significant (p = 0.178). Compared to non-carriers, PALB2 carriers has a tendency to appear in younger age (≤ 30 years) (25% vs 14.4%), human epidermal growth factor receptor-2 (HER2)-negative status (83.3% vs. 70.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%).ConclusionThe prevalence of the germline PALB2 pathogenic variants was approximately 0.77% in Chinese patients with BRCA1/2-negative early-onset breast cancer. Our findings is crucial for understanding population-specific genetic risks and offering insights that can enhance genetic counseling and genetic testing strategies in this population.

Spectrum and characteristics of germline PALB2 pathogenic variants among patients with early-onset breast cancer in China.

e22536 Background: Partner and localizer of BRCA2 ( PALB2) plays a critical role in homologous recombination repair and recognized as a breast cancer predisposition gene. Early age at onset of breast cancer is considered a hereditary high-risk factor. However, limited information is available about early-onset breast cancer in China. The objective of this study was to investigate the spectrum and characteristics of germline PALB2 pathogenic variants among this population. Methods: A total of 1556 patients with BRCA1/2-negative early-onset breast cancer were included. Peripheral blood samples were collected and all coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing. Results: The prevalence of germline PALB2 pathogenic variants was approximatel 0.77% in entire cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations, four nonsense mutations and one missense mutation. Except for PALB2 c.1056_1057del, which was detected twice, all other variants were detected once. In comparison to non-carriers, PALB2 carriers were more likely to be 30 years old or younger (25% vs. 14.4%), have a positive family history of breast or ovarian cancer (16.7% vs. 6.3%), exhibit metastatic lymph nodes (75% vs. 50.9%), belong to human epidermal growth factor receptor-2 (HER2) -negative and hormone receptor (HR) - positive subtype (75% vs 54.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%). Conclusions: The prevalence of the germline PALB2 pathogenic variants is approximately 0.77% in BRCA1/2 mutation-negative early-onset breast cancer patients in China. Our findings contribute additional insights into the spectrum and characteristics of PALB2 pathogenic variants in Chinese early-onset breast cancer patients, providing valuable information for this population. Key words: PALB2, Germline mutation, Genetic sequencing, early-onset breast cancer, China. [Table: see text]

Abstract PO5-07-01: A novel clinical risk score that can accurately predict the survival of young breast cancer patients: A UAE-based cohort study

Abstract Introduction: Breast cancer (BC) in women below the age of 40 accounts for approximately 7% of all BC cases. According to studies, BC in younger women is more likely to have negative tumor characteristics and outcomes compared to older women. The rate of early-onset breast cancer in the United Arab Emirates (UAE) is higher than in the Western population (24%, previously reported). Young breast cancer patients in the UAE have worse adverse features, including a higher grade, a larger tumor size, and lymph node involvement, as we reported previously. Therefore, combining several clinical indicators to predict recurrence risk in our unique, heterogeneous young breast cancer group is needed. Aim:The aim of this study is to develop a statistical machine learning model that can predict survival and the risk of recurrence in a young breast cancer population seen and treated in a large-volume tertiary cancer center in the United Arab Emirates (Tawam Hospital). Methods: Early-onset breast cancer patients from a retrospective observational cohort study were included in this study (N = 904). A broad range of clinical data was collected. A multivariate ridge Cox regression model was performed using age, histology, molecular type (ER,PR,HER-2 status), T-stage, N-Stage, M-stage, grade, and BMI, and the interaction term age*BMI at the time of diagnosis. The primary outcome was time-to-death. A novel breast cancer risk score (BCRS) was developed as the linear predictor of the fitted-ridge Cox regression model. Breast cancer patients were categorized into low, medium, and high risk using the 33th and 66th centiles of the novel BCRS. A univariate Cox regression model was performed with a categorized BCRS as a predictor of time-to-death. Hazard ratios (HR) with a 95% confidence interval (95% CI) were estimated. Kaplan-Meier (KM) curves were plotted and compared using the log-rank test. Time-dependent sensitivity and specificity were computed at five- and ten-year follow-ups, respectively. Statistical analyses were performed in R version 4.2.3. Results: The median age was 36 years (IQR: 32–38), and 64% were Arabic. Fifteen percent had an event with a median duration of follow-up of 15.4 years (95% CI: 13.6–17.1). The estimated HR of the categorized novel BCRS in a univariate Cox regression model was 1.968 (95% CI: 1.075- 3.601) and 8.040 (95% CI: 4.695–13.769) for the intermediate and high-risk groups as compared to the low-risk group, respectively. KM curves show a clear separation in terms of survival between the three risk groups, p< 0.0001 (Figure 1). A cutoff value of -1.733 gives a sensitivity of 93.8 and 90.6 with corresponding specificities of 31.42 and 31.31 at five- and ten-year follow-up, respectively. Conclusion: This is the first study in the region that uses clinical data that combines several clinical characteristics and aims to design a statistical machine learning model to predict the risk of death from breast cancer. Our novel model can be used in daily clinical practice to identify high risk breast cancer patients and aid clinical decision-making in patients with breast cancer. However, further validation studies are needed. Figure 1:KM curves of breast-cancer survival for patients with low-risk (BCRS in [-2.32, -1.63], black curve), intermediate-risk (BCRS in [-1.64, -1.25], red curve), and high-risk BCRS in [-1.26, 1.41], green curve). Citation Format: Aydah Al-Awadhi, Mohammed Hourani, Mawada Hussein, Fatima Alkindi, Lina Wahba, Abla AlAgha, Alaa Shoqeir, Mouza AlShebli, Atlal Abusanad, Amar Ahmad. A novel clinical risk score that can accurately predict the survival of young breast cancer patients: A UAE-based cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-07-01.

BRCA mutations: screening for germ-line founder mutations among early-onset Syrian breast cancer patients

BackgroundBreast cancer (BC) is the most common female cancers in many countries including Syria. Familial breast cancer or previous family cancer history are considered significant risk factors. Therefore, detecting the prevalence and founder mutations in the population facilitates genetic counselling, risk assessment and the development of a cost-effective screening strategy. In this study, we investigated the three germ-line founder mutations in the BRCA1/2 genes: [NM_007294.4 (BRCA1):c.68_69del (p.Glu23fs), NM_007294.4 (BRCA1):c.5266dup (p.Gln1756fs) and NM_000059.4 (BRCA2):c.5946del (p.Ser1982fs)], to examine their incidence and frequency in early-onset breast cancer cases and determine if they are connected to familial breast cancer. One hundred early diagnosed BC females (≤ 40 years old) with no other type of cancer were recruited. Genomic DNA was isolated from peripheral blood samples, and mutations were investigated using the Amplification-Created Restriction Site (ACRS) method.ResultsThe family history of cancer was observed in 61% of the cases, of which 35% were breast cancer; however, none of the screened mutations were detected among BC patients.ConclusionsThe investigated germ-line mutations were not common among Syrian female patients with early-onset BC and were not associated with familial BC. Other mutations in the BRCA1/2 genes or other genes may have a contributing role. Future studies and the need to launch nationwide mutation screening tests for BRCA 1/BRCA2 in the Syrian population are recommended.

Contribution of constitutional BRCA1 promoter methylation to early-onset and familial breast cancer patients from Pakistan.

Constitutional BRCA1 promoter methylation has been identified as a potential risk factor for breast cancer (BC) in the Caucasian population. However, this data is lacking for BC patients of Asian origin. Therefore, we assessed the contribution of constitutional BRCA1 promoter methylation in Pakistani BC patients. A total of 385 BRCA1/2-negative index BC patients (197 early-onset BC (≤ 30years), 152 familial BC, 17 familial BC and ovarian cancer, 19 male BC) and 107 healthy controls were screened for the constitutional BRCA1 promoter methylation by methylation-sensitive high-resolution melting assay. Overall, 131 patients displayed triple-negative BC (TNBC) and 254 non-TNBC phenotypes. The prevalence of BRCA1 promoter methylation was calculated based on clinicopathological characteristics using univariable and multivariable logistic regression models. Constitutional BRCA1 promoter methylation was identified in 19.5% (75/385) of BC patients and 13.1% (14/107) of controls. The frequency of methylation was higher in early-onset BC (23.4% vs. 13.1%, P = 0.035) and TNBC patients (29.0% vs. 13.1%, P = 0.004) compared to controls. Methylation was also more prevalent in patients with high-grade than low-grade tumors (21.7% vs. 12.2%, P = 0.034) and progesterone receptor (PR)-negative than PR-positive tumors (26.0% vs. 13.9%, P = 0.004). Constitutional BRCA1 promoter methylation remained independently associated with TNBC phenotype (odds ratio 1.99; 95% CI 1.12-3.54; P = 0.02) after adjusting for BC diagnosis age, tumor grade, ER, and PR status. Constitutional BRCA1 promoter methylation is associated with TNBC and can serve as a non-invasive blood-based biomarker for Pakistani TNBC patients.

ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways—lessons from breast cancer patients

It has been well-established that mutations in BRCA1 and BRCA2, compromising functions in DNA double-strand break repair (DSBR), confer hereditary breast and ovarian cancer risk. Importantly, mutations in these genes explain only a minor fraction of the hereditary risk and of the subset of DSBR deficient tumors. Our screening efforts identified two truncating germline mutations in the gene encoding the BRCA1 complex partner ABRAXAS1 in German early-onset breast cancer patients. To unravel the molecular mechanisms triggering carcinogenesis in these carriers of heterozygous mutations, we examined DSBR functions in patient-derived lymphoblastoid cells (LCLs) and in genetically manipulated mammary epithelial cells. By use of these strategies we were able to demonstrate that these truncating ABRAXAS1 mutations exerted dominant effects on BRCA1 functions. Interestingly, we did not observe haploinsufficiency regarding homologous recombination (HR) proficiency (reporter assay, RAD51-foci, PARP-inhibitor sensitivity) in mutation carriers. However, the balance was shifted to use of mutagenic DSBR-pathways. The dominant effect of truncated ABRAXAS1 devoid of the C-terminal BRCA1 binding site can be explained by retention of the N-terminal interaction sites for other BRCA1-A complex partners like RAP80. In this case BRCA1 was channeled from the BRCA1-A to the BRCA1-C complex, which induced single-strand annealing (SSA). Further truncation, additionally deleting the coiled-coil region of ABRAXAS1, unleashed excessive DNA damage responses (DDRs) de-repressing multiple DSBR-pathways including SSA and non-homologous end-joining (NHEJ). Our data reveal de-repression of low-fidelity repair activities as a common feature of cells from patients with heterozygous mutations in genes encoding BRCA1 and its complex partners.

Whole-exome sequencing of BRCA-negative breast cancer patients and case–control analyses identify variants associated with breast cancer susceptibility

BackgroundFor the majority of individuals with early-onset or familial breast cancer referred for genetic testing, the genetic basis of their familial breast cancer remains unexplained. To identify novel germline variants associated with breast cancer predisposition, whole-exome sequencing (WES) was performed.MethodsWES on 290 BRCA1/BRCA2-negative Singaporeans with early-onset breast cancer and/or a family history of breast cancer was done. Case–control analysis against the East-Asian subpopulation (EAS) from the Genome Aggregation Database (gnomAD) identified variants enriched in cases, which were further selected by occurrence in cancer gene databases. Variants were further evaluated in repeated case–control analyses using a second case cohort from the database of Genotypes and Phenotypes (dbGaP) comprising 466 early-onset breast cancer patients from the United States, and a Singapore SG10K_Health control cohort.ResultsForty-nine breast cancer-associated germline pathogenic variants in 37 genes were identified in Singapore cases versus gnomAD (EAS). Compared against SG10K_Health controls, 13 of 49 variants remain significantly enriched (False Discovery Rate (FDR)-adjusted p < 0.05). Comparing these 49 variants in dbGaP cases against gnomAD (EAS) and SG10K_Health controls revealed 23 concordant variants that were significantly enriched (FDR-adjusted p < 0.05). Fourteen variants were consistently enriched in breast cancer cases across all comparisons (FDR-adjusted p < 0.05). Seven variants in GPRIN2, NRG1, MYO5A, CLIP1, CUX1, GNAS and MGA were confirmed by Sanger sequencing.ConclusionsIn conclusion, we have identified pathogenic variants in genes associated with breast cancer predisposition. Importantly, many of these variants were significant in a second case cohort from dbGaP, suggesting that the strategy of using case–control analysis to select variants could potentially be utilized for identifying variants associated with cancer susceptibility.

TP53 Pathogenic Variants in Early-Onset Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and Li-Fraumeni-like Syndromes.

TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil’s South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2–11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.

Novel Insights From the Germline Landscape of Breast Cancer in Brazil.

IntroductionBreast cancer patients with germline pathogenic variants may benefit from risk-reducing surgeries, intensive screening, and targeted cancer therapies. There is a paucity of data regarding prevalence and distribution of germline pathogenic variants in the Brazilian population. Our primary endpoint was the description of prevalence and distribution of germline pathogenic variants among breast cancer patients who underwent next-generation sequencing (NGS) panel testing. Secondary endpoint was the assessment of predictive factors of a positive test.MethodsWe analyzed NGS results, personal, and family history data from a prospectively collected cohort of breast cancer patients from August 2013 to May 2019. Exact logistic regression was used to perform multivariable analysis.ResultsOf 370 breast cancer patients, we found 59 pathogenic variants in 57 (15%) patients. Pathogenic variants were identified in BRCA1 (24%), ATM (14%), BRCA2 (10%), TP53 (8%), PALB2 (8%), CHEK2 (7%), CDH1 (3%), RAD51C (3%), MITF (2%), PMS2 (2%), RAD51D (2%), and TERT (2%). Monoallelic MUTYH pathogenic variants were found in 15%. After multivariable analysis, age of diagnosis (OR 0.89, 95% CI: 0.81–0.95, for each year increase), triple-negative subtype (OR 17.2, 95% CI: 3.74–114.72), and number of breast cancers in the family (OR 2.46, 95% CI 1.57–4.03, for each additional case) were associated with BRCA1 pathogenic variants. In the present study, a quarter of triple-negative breast cancer patients harbored a germline pathogenic variant and two-thirds of those were BRCA1 carriers.ConclusionsPrevalence and distribution of germline pathogenic variants in this Brazilian sample of breast cancer patients are mostly similar to other populations. However, there is a trend to an overrepresentation of TP53 pathogenic variants that merits confirmation in further studies. Early-onset breast cancer patients should be offered genetic counseling, particularly those with triple-negative subtype.

Mutations in exon region of BRCA1-related RING domain 1 gene and risk of breast cancer.

BackgroundBRCA1‐associated RING Domain 1 (BARD1) is an important gene related to breast cancer development. However, the role of BARD1 mutations in breast cancer remains inconclusive. This study is to investigate the relationship between exon mutations of BARD1 gene and the risk of early‐onset breast cancer.MethodsTotally, 60 cases of early‐onset breast cancer patients (age 30–40 years) and 240 healthy women (age 30–40 years) were enrolled. Exon mutations of BARD1 were detected and analyzed by direct sequencing and SNaPshot.ResultsThe risk of breast cancer was increased by 3.475 times in carriers with deletion mutation at rs28997575 site of BARD1 (aOR1 = 3.475, 95%CI = 1.302–9.276) (p = 0.013). The risk of breast cancer in carriers with GC genotype at rs2229571 site of BARD1 was reduced by 72.6% (aOR1 = 0.274, 95%CI = 0.134–0.562) (p = 0.001), and that in carriers with CC genotype was reduced by 82.8% (aOR1 = 0.172, 95%CI = 0.076–0.392) (p = 0.001). After stratification with family history, the difference of rs2229571 site mutation genotype was statistically significant (OR = −2.169, 95%CI = 0.016–0.828, p = 0.032). Additionally, the frequency distribution of breast cancer family history in the case group (15%) was significantly more than that in the control group (6.7%) (p = 0.037).ConclusionThe deletion mutation at rs28997575 locus of the BARD1 gene can significantly increase the risk of breast cancer. The mutation genotype of rs2229571 locus can significantly reduce the risk of breast cancer. Family history is associated with BARD1 gene polymorphism. A family history of breast cancer may be a risk factor for breast cancer.

DNA Repair Genes as Drug Candidates for Early Breast Cancer Onset in Latin America: A Systematic Review.

The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.

Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients

BackgroundThe data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited.MethodsWe determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing.ResultsGermline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS.ConclusionsTP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.

Breast cancer in West Africa: molecular analysis of BRCA genes in early-onset breast cancer patients in Burkina Faso

BackgroundBreast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among women in Africa after cervical cancer. Even if the epidemiological data are now aligned with those relating to industrialized countries, the knowledge concerning breast cancer in Africa, particularly in Western Africa, still lack clinical data, medical treatments, and the evaluation of genetic and non-genetic factors implicated in the etiology of the disease. The early onset and the aggressiveness of diagnosed breast cancers in patients of African ancestry strongly suggest that the genetic risk factor may be a key component, but so far, very few studies on the impact of germ line mutations in breast cancer in Africa have been conducted, with negative consequences on prevention, awareness and patient management. Through Next Generation sequencing (NGS), we analyzed all of the coding regions and the exon–intron junctions of BRCA1 and BRCA2 genes—the two most important genes in hereditary breast cancer—in fifty-one women from Burkina Faso with early onset of breast cancer with or without a family history.ResultsWe identified six different pathogenic mutations (three in BRCA1, three in BRCA2), two of which were recurrent in eight unrelated women. Furthermore, we identified, in four other patients, two variants of uncertain clinical significance (VUS) and two variants never previously described in literature, although one of them is present in the dbSNP database.ConclusionsThis is the first study in which the entire coding sequence of BRCA genes has been analyzed through Next Generation Sequencing in Burkinabe young women with breast cancer. Our data support the importance of genetic risk factors in the etiology of breast cancer in this population and suggest the necessity to improve the genetic cancer risk assessment. Furthermore, the identification of the most frequent mutations of BRCA1 and BRCA2 in the population of Burkina Faso will allow the development of an inexpensive genetic test for the identification of subjects at high genetic cancer risk, which could be used to design personalized therapeutic protocols.

Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.

New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients.

In Russia, more than 50,000women are diagnosed with breast cancer (BC) every year. Russia is a multinational country- about 200ethnic groups live on its territory. Khakass, Buryats, Tuvans and other ethnic groups show higher rate of increase in BC incidence and a younger age of first diagnosed BC compared to Caucasian ethnicities. We focused on Tuvan ethnic group to find specific genetic aberrations associated with BC. There are no BC prevention models as well as standards for the treatment of inherited BC in Tuvans. In this context, the search for genetic markers of early cancer detection and the development of criteria for therapy response are relevant. To identify hereditary mutations in BC-associated genes in Tuvan women. 24patients with early-onset BC (range, 25to 46years) were enrolled in the study. Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit covering 27genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53and XRCC2). Next-generation sequencing was performed using the Illumina NextSeq500System. In our study, one pathogenic mutation was detected in BRCA1 (rs80357868) gene (prevalence of 4%, 1/24). We identified the truncating 3875_3878delGTCT mutation of BRCA1gene in Tuvans BC patient aged 34years. We also detected three mutations that were probably damaging by PolyPhen2and/or deleterious by SIFT in ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes. To the best of our knowledge, this is the first report that describes the highly pathogenic variant in the BRCA1gene (rs80357868) and possibly damaging (PolyPhen2) germline variants in the ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes in young Tuvans BC patient.

Abstract PS7-81: Clinical and pathological features of very early-onset breast cancer and treatment challenges on public health care system at a cancer center in Brazil

Abstract Background: Even though breast cancer is uncommon in women ≤ age 35, women in this group are more likely to present aggressive cancer subtypes, advanced clinical stage at diagnosis and pathogenic variants (PV) in cancer susceptibility genes. Higher recurrence and mortality rates in very early-onset breast cancer patients may be related to differences in tumor biology, mutation status, clinical or treatment features. Management of those women should comprehend dedicated approach and standard care that are often not available on cancer care centers at low-middle income countries. We aim to describe the clinical and pathological factors associated with very early-onset breast cancer patients and the challenges associated with treatment of those women in a public health facility in Brazil. Methods: Retrospective review of 748 patients diagnosed and treated at the biggest surgical center for breast cancer in Brasilia - Brazil between 2015 and 2020 was performed and 54 patients with cancer diagnosis ≤ age 35 were identified. Pathological and clinical characteristics as well as treatment information were collected from medical and electronic patients’ records. Bivariate and multivariate analyzes were performed. Findings: Median age at diagnosis was 31.9 years old (23 to 35). 44% had a positive familial history for HBOC. 20% presented first period &amp;lt;12 years of age and 61% and 53% had first childbirth &amp;lt; 30 years and breastfed for over 6 months, respectively. Only 10% had a BMI index over 30, and 37% were overweight. The distribution of BC stage at diagnosis was I (9.3%), II (51.9%), III (29.6%) and IV (3.7%). The most common were invasive carcinoma of no special type (98%) and malignant phyllodes (2%) and 10.9%, 50.9% and 27.3% were grades 1, 2 and 3, respectively. BC subtypes were as follows: Luminal A 18.5%, Luminal B 31.5%, HER2 positive 24.1% and Triple negative 25.9%. With a mean follow-up of 31.94 months, the overall survival rate was 93%, with a recurrence-free survival rate of 72.1%.Although all patients met the criteria for germline testing, only 25.9% had access, with two BRCA1, four BRCA 2, one CHECK2 and one TP53 PV detected. 27.8% had BCS as surgical treatment and 53.7% e 13% had unilateral and bilateral mastectomy. There was an increased rate of bilateral mastectomy on the last 8 years. 73.6% were treated with neoadjuvant chemotherapy (NC) and mean interval between NC and surgery was 61.1 days (19-370). 63% had radiotherapy and the mean interval between previous treatment (chemotherapy or surgery) and radiotherapy was 93.8 days (56-150). None of the HER2 positive patients were exposed to dual HER2 blockade and there was no adjuvant treatment with T-DM1 or capecitabine when pCR was not achieved. Only 22% of the women with hormone receptor tumors were exposed to ovarian suppression alongside hormone therapy. Of the 54 patients, 27.9% relapsed, 18.6% distant recurrence, 9.3% local. The most common sites of metastasis was bone and liver (6.8% each) followed by lung and central nervous system (3.4% and 1.7%). Conclusions: Previous studies showed that breast cancer is diagnosed at an earlier age among Brazilian patients. BC is often detected when symptomatic and therefore a significant proportion is diagnosed at more advanced clinical stages. These findings alongside the restrict acess to genetic counseling and the delay on treatment in the public healthcare system are a clear indication of the challenges for achieving standard care for those patients and could have a significant impact on survival outcomes. These data combined indicate the need for supportive care program for young women with breast cancer. Citation Format: Natasha Garcia Caldas, Karoline Evangelista Souza, Thais Karla Vivan, Vinicius Xavier Santana, Mauro Pinto Passos, Natalia Polidorio. Clinical and pathological features of very early-onset breast cancer and treatment challenges on public health care system at a cancer center in Brazil [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-81.

Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

BackgroundThe RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan.MethodsComprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines.ResultsOne novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls.ConclusionsOur data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.

The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer.

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco

BackgroundTo date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco.MethodsThirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform.ResultsOverall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer.ConclusionOur data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.