Early-onset Breast Cancer Research Articles

Classification of Early Breast Cancer using Convolutional Neural Networks

Breast cancer is a life-threatening disease that impacts millions of people worldwide, necessitating heightened awareness and effective early detection strategies. Current methods for determining the presence and type of breast cancer in a clinical breast exam conducted by healthcare providers may be inaccurate, imprecise, and prone to error. The goal of this research project is to offer a second opinion for physicians to predict whether or not a patient has early onset breast cancer through a machine learning model developed from an image dataset, to significantly reduce the error in breast cancer staging, making the process more efficient in healthcare. Early detection is crucial for successful treatments of breast cancer, as treatment options in late-stage diagnosis of breast cancer can have a much worse prognosis. In the US, 240,000 cases of breast cancer are diagnosed per year in both men and women with a mortality rate of approximately 42,000 per year. [1] To approach this problem, I have tested an MLP Classifier, Logistic Regression, Ridge Classifier, Random Forest Classifier, Decision Tree Classifier, Support Vector Classifier, and trained a Convolutional Neural Network to compare various results and determine the best accuracy. The Convolutional Neural Network yielded impressive outcomes, reaching up to 79% testing accuracy and 98% training accuracy. The final model exhibits the capability to identify early signs of breast cancer and differentiate between malignant and benign tumours with relatively high accuracy showing the potential of AI in combination with medical imaging that can assist medical staff in diagnosis.

Gynecologic Care of Black Breast Cancer Survivors.

Black patients suffer from breast cancer-related racial health disparities, which could have implications on their gynecologic care. This review explores considerations in the gynecologic care of Black breast cancer survivors. Black people have a higher risk of leiomyoma and endometrial cancer, which could confound bleeding patterns such as in the setting of tamoxifen use. As Black people are more likely to have early-onset breast cancer, this may have implications on long-term bone and heart health. Black patients may be more likely to have menopausal symptoms at baseline and as a result of breast cancer treatment. Furthermore, Black patients are less likely to utilize assisted reproductive technology and genetic testing services. It is important for healthcare providers to be well-versed in the intersections of breast cancer and gynecologic care. Black breast cancer survivors may have unique considerations for which practitioners should be knowledgeable.

Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand

Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.

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.

Epithelioid angiomyolipoma of the liver in a patient with Li-Fraumeni syndrome: a case report

BackgroundEpithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that predominantly consists of epithelioid cells and belongs to the perivascular epithelioid cell neoplasm (PEComa) family. The majority of EAMLs arise in the kidneys, and primary hepatic EAML appears to be much less common than renal EAML. Most PEComas arise sporadically, but may be associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder characterized by germline mutations in the TSC1 or TSC2 genes. However, PEComas have previously been reported in five patients with Li-Fraumeni syndrome (LFS), which is an inherited cancer susceptibility disorder resulting from germline mutations in the TP53 tumor suppressor gene.Case presentationWe report a 49-year-old female patient with hepatic EAML and pancreatic cancer. Because she had previously been diagnosed with bilateral breast cancer at the age of 30, we performed a comprehensive genetic analysis to identify genetic alterations associated with any cancer predisposition syndrome. Whole-exome sequencing of a blood sample identified a heterozygous germline variant of TP53 (NM_000546.5):c.708C>A, and targeted next-generation sequencing of liver EAML and pancreatic cancer tissue samples demonstrated the same TP53 (NM_000546.5):c.708C>A variant in both. This, plus the patient’s history of early-onset breast cancer, met the 2015 version of the Chompret criteria for diagnosis of LFS.ConclusionsThere have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS.

Association of Genetic Markers with the Risk of Early-Onset Breast Cancer in Kazakh Women.

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10-6) and MGAT5 gene (p = 8.4 × 10-6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10-4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction.

Male breast cancer: No evidence for mosaic BRCA1 promoter methylation involvement

Breast cancers (BC) are rare in men and are often caused by constitutional predisposing factors. In women, mosaic BRCA1 promoter methylations (MBPM) are frequent events, detected in 4–8% of healthy subjects. This constitutional epimutation increases risk of early-onset and triple-negative BC. However, the role of MBPM in male BC predisposition has never been assessed. We screened 40 blood samples from men affected by BC, and performed extensive tumour analysis on MBPM-positive patients. We detected two patients carrying MBPM. Surprisingly, tumour analysis revealed that neither of these two male BCs were caused by the constitutional BRCA1 epimutations carried by the patients.

Clinical and functional analysis of the germline TP53 p.K164E acetylation site variant.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

Granulomatous lobular mastitis co-existing with ductal carcinoma in situ: Report of three cases and review of the literature

Granulomatous lobular mastitis (GLM) is a benign and infrequent chronic breast ailment. Although this lesion can be clinically and radiographically mistaken for early-onset breast cancer, it is a rare occurrence for the two to coexist. This report describes three such cases. In all three patients, the primary signs and symptoms were related to the formation of diffuse breast masses or abscesses. Breast ultrasound and MRI revealed glandular edema and dilated breast ducts. The biopsies of all lesions exhibited both granulomatous inflammation confined to the lobules of the breast, abundant interstitial inflammatory cell infiltrates, and apparently cancerous cells located in dilated ducts with intact basement membranes. The surgically excised specimens confirmed the diagnosis of GLM and ductal carcinoma in situ (DCIS) in all three patients who underwent breast mass resection. By clinical imaging and clinical manifestations, GLM may obscure a concurrent DCIS, as highlighted by the cases reported herein.

Reduced Psychosocial Well-Being among the Children of Women with Early-Onset Breast Cancer.

Approximately 27% of female breast cancer patients are diagnosed before the age of 55, a group often comprising mothers with young children. Maternal psychosocial well-being significantly impacts these children's psychosocial well-being. This study assesses the well-being of children with mothers who have early-onset breast cancer. We examined the eldest child (up to 15 years old) of women with nonmetastatic breast cancer (<55 years old, mean age: 40) enrolled in the mother-child rehab program 'get well together'. Using maternal reports on children's well-being (the Strengths and Difficulties Questionnaire; SDQ), we describe the prevalence of abnormally high SDQ scores and identify protective and risk factors via linear regression. The mean SDQ scores of 496 children (4-15 years old, mean age: 8) fell below the thresholds, indicating psychosocial deficits. However, most SDQ scores deviated negatively from the general population, especially for emotional problems, with one in ten children displaying high and one in five displaying very high deficits. Female sex, more siblings, a positive family environment and maternal psychosocial well-being were protective factors for children's psychosocial well-being. Children of mothers with breast cancer may benefit from improved maternal well-being and family support. Further research is needed to identify appropriate interventions.

Association of Germline Variation in Driver Genes with Breast Cancer Risk in Chilean Population.

Cancer is a genomic disease, with driver mutations contributing to tumorigenesis. These potentially heritable variants influence risk and underlie familial breast cancer (BC). This study evaluated associations between BC risk and 13 SNPs in driver genes MAP3K1, SF3B1, SMAD4, ARID2, ATR, KMT2C, MAP3K13, NCOR1, and TBX3, in BRCA1/2-negative Chilean families. SNPs were genotyped using TaqMan Assay in 492 cases and 1285 controls. There were no associations between rs75704921:C>T (ARID2); rs2229032:A>C (ATR); rs3735156:C>G (KMT2C); rs2276738:G>C, rs2293906:C>T, rs4075943T:>A, rs13091808:C>T (MAP3K13); rs178831:G>A (NCOR1); or rs3759173:C>A (TBX3) and risk. The MAP3K1 rs832583 A allele (C/A+A/A) showed a protective effect in families with moderate BC history (OR = 0.7 [95% CI 0.5-0.9] p = 0.01). SF3B1 rs16865677-T (G/T+T/T) increased risk in sporadic early-onset BC (OR = 1.4 [95% CI 1.0-2.0] p = 0.01). SMAD4 rs3819122-C (A/C+C/C) increased risk in cases with moderate family history (OR = 2.0 [95% CI 1.3-2.9] p ≤ 0.0001) and sporadic cases diagnosed ≤50 years (OR = 1.6 [95% CI 1.1-2.2] p = 0.006). SMAD4 rs12456284:A>G increased BC risk in G-allele carriers (A/G + G/G) in cases with ≥2 BC/OC cases and early-onset cases (OR = 1.2 [95% CI 1.0-1.6] p = 0.04 and OR = 1.4 [95% CI 1.0-1.9] p = 0.03, respectively). Our study suggests that specific germline variants in driver genes MAP3K1, SF3B1, and SMAD4 contribute to BC risk in Chilean population.

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Diagnostic delay among young women with breast cancer.

117 Background: Breast cancer in women under 40 is uncommon, but often presents with greater disease burden and worse survival compared to the post-menopausal population. Given its infrequence, it is not well-understood how young patients initiate contact with care and how they are investigated prior to establishing the diagnosis. Whether young women experience diagnostic delay and whether it might impact survival is unclear. We aimed to describe the presentation of breast cancer among women &lt;40 and to understand the diagnostic timeline using patient-reported outcomes. Methods: We evaluated patients in the Reducing the Burden of Breast Cancer in Young Women (RUBY) cohort, a pan-Canadian study recruiting women &lt;40 with breast cancer at the time of diagnosis. Five online surveys detailing demographics, medical/family history and the diagnostic journey, distributed by e-mail at the time of recruitment, were used. All subjects who completed the surveys from 2015-2022 were included. A “patient delay” was considered &gt;4 weeks from onset of symptoms to first contact with the healthcare system. A “system delay” was considered &gt;3 weeks from presentation to first investigation, based on Canadian Partnership Against Cancer screening guidelines. Analysis was conducted using descriptive statistics. Results: There were 1148 patients included for analysis. Median age (IQR) was 37 (33.9, 39.0). Eighty-nine percent of patients had a symptom prompting assessment, of which most had a palpable mass (77.3%), and 27.7% had a painful mass. The median (IQR) number of weeks that patients waited was 2.0 (1.0, 8.0), and 364 patients (31.7%) experienced a patient delay. Most patient delays were attributed to lack of awareness of associated symptoms: 27.7% of patients were not concerned about their symptom and 3.9% were falsely reassured by practitioners. Other reasons included difficulty accessing timely care (3.6%; 37 patients) and conflicting priorities (2.1%; 21 patients). One hundred sixteen patients (10.1%) experienced a system delay. When asked about perceived timeliness of diagnosis, only 248 patients (24.4%) felt their time to assessment was not fast enough. Conclusions: The majority of young women with breast cancer present with palpable, often painful masses. A significant proportion of women experienced a patient delay, suggesting opportunities for increased education regarding presentation of early-onset breast cancer; After presentation to care, most women were investigated in a timely manner.

Detection of Breast Cancer from Mammogram using Convolution Neural Network

Abstract: Breast cancer is the leading cause of cancer among women. In the last few years, the number of cases of breast cancer has skyrocketed among younger women. Detection of breast cancer during the initial stages can greatly reduce the risk of fatality. Mammograms which are X-ray images of breast tissues are used extensively by doctors to determine the early onset of breast cancer. However, due to human error, a lack of resources and knowledge can result in inaccurate predictions which can prove fatal. The power of Artificial Intelligence to process and predict images has greatly increased in the past few years. Many modern medical devices utilize the power of sophisticated AI algorithms to aid in detecting and predicting the early onset of breast cancer. In this paper, we demonstrate how we can utilize a convolution neural network to predict the early onset of breast cancer and help solve the issue of inaccurate detection of cancer cells from mammogram images.

Molecular profiling of BRCA1 and BRCA2 genes in Turkish patients with early-onset breast cancer

BackgroundEarly-onset breast cancer (EOBC) is a specific condition that affects women under the age of 45. BRCA pathogenic/likely pathogenic (P/LP) germline variants have been demonstrated to be harbored in a subgroup of EOBC individuals, and BRCA-positive genetic result offers an option to ensure more specified therapeutic implications. Establishing comprehensive BRCA1/2 genetic testing, including both the detection of small-scale mutations and large genomic rearrangements (LGRs), is needed for risk assessment and clinical management. In this study, we described a Turkish EOBC cohort along with their clinico-pathological characteristics and BRCA1/2 mutational profiles. A total of 67 unrelated patients were enrolled. Both next-generation sequencing (NGS)-based gene panel and multiplex ligation-dependent probe amplification (MLPA) were performed for BRCA1/2 variant identification. Patients' family medical history and hormone receptor status of the tumors were also recorded.Results14 (20.90%) patients were found to carry BRCA P/LP germline variants. (Nine were BRCA2-positive, and five were BRCA1-positive.) Two novel BRCA2 variants were detected. No significant differences were found between BRCA-positive vs. BRCA-negative or BRCA1-positive vs. BRCA2-positive for hormonal status and family history.ConclusionsBRCA1/2 genes represent a predominant part of the genetic landscape of EOBC. Our results expand the spectrum of BRCA1/2 variants and provide knowledge of the BRCA1/2 variant prevalence in our cohort.

Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity.

Breast cancer (BC) is the most common type of cancer among women in Kazakhstan. To date, little data are available on the spectrum of genetic variation in Kazakh women with BC. We aimed to identify population-specific genetic markers associated with the risk of developing early-onset BC and test their association with clinical and prognostic factors. The study included 224 Kazakh women diagnosed with BC (≤40 age). Entire coding regions (>1700 exons) and the flanking noncoding regions of 94 cancer-associated genes were sequenced from blood DNA using MiSeq platform. We identified 38 unique pathogenic variants (PVs) in 13 different cancer-predisposing genes among 57 patients (25.4%), of which 6 variants were novel. In total, 12 of the 38 distinct PVs were detected recurrently, including BRCA1 c.5266dup, c.5278-2del, and c.2T>C, and BRCA2 c.9409dup and c.9253del that may be founder in this population. BRCA1 carriers were significantly more likely to develop triple-negative BC (OR = 6.61, 95% CI 2.44-17.91, p = 0.0002) and have family history of BC (OR = 3.17, 95% CI 1.14-8.76, p = 0.03) compared to non-carriers. This study allowed the identification of PVs specific to early-onset BC, which may be used as a foundation to develop regional expertise and diagnostic tools for early detection of BC in young Kazakh women.

Early-Onset Breast Cancer and Geospatial Indicators of Exposures in the Arkansas Rural Community Health Study (ARCH)

Early-Onset Breast Cancer and Geospatial Indicators of Exposures in the Arkansas Rural Community Health Study (ARCH)

Interplay of Mendelian and polygenic risk factors in Arab breast cancer patients

BackgroundBreast cancer patients from the indigenous Arab population present much earlier than patients from Western countries and have traditionally been underrepresented in cancer genomics studies. The contribution of polygenic and Mendelian risk toward the earlier onset of breast cancer in the population remains elusive.MethodsWe performed low-pass whole genome sequencing (lpWGS) and whole-exome sequencing (WES) from 220 female breast cancer patients unselected for positive family history from the indigenous Arab population. Using publicly available resources, we imputed population-specific variants and calculated breast cancer burden-sensitive polygenic risk scores (PRS). Variant pathogenicity was also evaluated on exome variants with high coverage.ResultsVariants imputed from lpWGS showed high concordance with paired exome (median dosage correlation: 0.9459, Interquartile range: 0.9410–0.9490). After adjusting the PRS to the Arab population, we found significant associations between PRS performance in risk prediction and first-degree relative breast cancer history prediction (Spearman rho=0.43, p = 0.03), where breast cancer patients in the top PRS decile are 5.53 (95% CI 1.76–17.97, p = 0.003) times more likely also to have a first-degree relative diagnosed with breast cancer compared to those in the middle deciles. In addition, we found evidence for the genetic liability threshold model of breast cancer where among patients with a family history of breast cancer, pathogenic rare variant carriers had significantly lower PRS than non-carriers (p = 0.0205, Mann-Whitney U test) while for non-carriers every standard deviation increase in PRS corresponded to 4.52 years (95% CI 8.88–0.17, p = 0.042) earlier age of presentation.ConclusionsOverall, our study provides a framework to assess polygenic risk in an understudied population using lpWGS and identifies common variant risk as a factor independent of pathogenic variant carrier status for earlier age of onset of breast cancer among indigenous Arab breast cancer patients.

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.

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

BackgroundCancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung.MethodsExome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case–control association analyses were performed.ResultsAltogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations.ConclusionsWe have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.