Mutations In Susceptibility Genes Research Articles

Intelligent treatment system based on bioinformatics and neuro-immune-digestive tract diseases

There are currently many clinical issues plaguing digestive oncologists, including the impact of dietary habits on the occurrence of early gastrointestinal cancer, the association between irritable bowel syndrome, ulcerative colitis, and early gastrointestinal cancer, the expected changes in gastrointestinal cancer after IBS, IBD, and susceptibility gene mutations, and the mechanisms by which susceptibility gene mutations in gastrointestinal cancer lead to different diseases. Meanwhile, as a carcinogen, betel nut is also prone to cancer and emotional disorders, and there are also many doctor-patient conflicts in the current clinical treatment of digestive tract tumors. To address the aforementioned issues, the research team analyzed dietary habits data using SOM clustering algorithm and isolated forest algorithm. Based on bioinformatics, new therapies have been developed for the pathogenesis and immune pathways of various cancers in the digestive system. Using network pharmacology methods, explore the toxicological mechanism of betel nut and its mechanism in mediating emotional disorders. Molecular docking is used to elucidate drug prediction. Based on four AI algorithms, the occurrence of gastrointestinal cancer was predicted through dietary habits. Using computer vision technology to address the deficiencies in early clinical reporting of cancer. This article provides clinical doctors with new treatment tools.

The relationship between clinical characteristics and pathological features in patients with pheochromocytomas/paragangliomas

Objective: To explore the correlation between clinical characteristics and pathological features in patients with pheochromocytoma/paraganglioma (PPGLs). Methods: A case series study. A retrospective analysis was conducted on patients with single and primary PPGLs after postoperative pathological diagnosis who were admitted to Peking Union Medical College Hospital between January 2019 and December 2022. The patients were divided into the Ki-67<3% group and the Ki-67≥3% group with Ki-67 proliferation index of 3% as the threshold. The relationship between clinical and pathological characteristics of PPGLs was analyzed. Results: A total of 399 PPGLs patients were included, with 177 males and 222 females, aged [M(Q1, Q3)] 45.0(35.5, 53.0) years. Among them, 226 (56.6%) cases originated from the adrenal gland, while 104 cases (26.1%) from the retroperitoneum. 20.9% (27/129) of the patients were found to harbor germline mutations of susceptibility genes, with SDHB mutations being the most common (10.1%, 13/129). The Ki-67 staining was performed on 302 cases, with a Ki-67 proliferation index [M(Q1, Q3)] of 2.0% (1.0%, 3.0%). There were 194 cases in Ki-67<3% group and 108 cases in Ki-67≥3% group. Compared with the patients in Ki-67<3% group, the age of onset in Ki-67≥3% group was younger (P=0.029). Compared with the patients with paragangliomas without SDHB or Cluster 1A-related gene mutations, positive 131I-meta-iodobenzylguanidine (131I-MIBG) imaging or negative O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry staining, those with SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging or positive MGMT immunohistochemistry staining had a higher Ki-67 index (all P<0.05). Compared with adrenal pheochromocytoma, retroperitoneal paragangliomas had a higher proportion of SDHB mutations and a higher proportion of normetanephrine (NMN) secretory types (all P<0.05). Compared with adrenal pheochromocytoma, the maximum diameter of head and neck paraganglioma tumors was smaller [3.0 (1.9, 3.8) cm vs 4.7 (3.4, 6.4) cm, P<0.001] and the proportion of Ki-67≥3% was higher (61.3% vs 33.8%, P=0.007). Conclusions: PPGLs patients with earlier onset age, SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging, or positive MGMT immunohistochemistry staining tend to have a higher Ki-67 index. Head and neck tumors, though smaller, exhibit a higher proliferation potential.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2−) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17–0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

FOXM1 c.1205C > A mutation is associated with unilateral Moyamoya disease and inhibits angiogenesis in human brain endothelial cells.

Unilateral moyamoya disease (MMD) represents a distinct subtype characterised by occlusive changes in the circle of Willis and abnormal vascular network formation. However, the aetiology and pathogenesis of unilateral MMD remain unclear. In this study, genetic screening of a family with unilateral MMD using whole-genome sequencing helped identify the c.1205C > A variant of FOXM1, which encodes the transcription factor FOXM1 and plays a crucial role in angiogenesis and cell proliferation, as a susceptibility gene mutation. We demonstrated that this mutation significantly attenuated the proangiogenic effects of FOXM1 in human brain endothelial cells, leading to reduced proliferation, migration, and tube formation. Furthermore, FOXM1 c.1205C > A results in increased apoptosis of human brain endothelial cells, mediated by the downregulation of the transcription of the apoptosis-inhibiting protein BCL2. These results suggest a potential role for the FOXM1 c.1205C > A mutation in the pathogenesis of unilateral MMD and may contribute to the understanding and treatment of this condition.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Knowledge of BRCA gene among young Pakistani adults: A short report.

A total of 271 young Pakistani adults responded to a selfdesigned multiple choice-based questionnaire (α = 0.83) which was then used to assess the levels of knowledge regarding breast cancer susceptibility (BRCA) gene mutation. Overall knowledge levels were assessed using the sum score of each response; any possible significance between knowledge scores and educational backgrounds as well as gender were also tested. The results show that 161 (63.9%) of the sample population had awareness about BRCA gene mutation. Knowledge scores were comparable across both groups (medical and non-medical educational backgrounds) with 20 (13.8%) of medical and 14 (13.5%) of non-medical respondents demonstrating a high level of knowledge about the BRCA gene mutation and its testing. Neither gender nor educational background had a significant influence on knowledge scores. The results from this report suggest that awareness regarding BRCA gene was adequate, while knowledge levels were noted to be poor among the sample population.

The Low Tumorigenic Risk and Subtypes of Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

Background: Clinical application of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a promising approach for the treatment of heart diseases. However, the tumorigenicity of hiPSC-CMs remains a concern for their clinical applications and the composition of the hiPSC-CM subtypes need to be clearly identified. Methods: In the present study, hiPSC-CMs were induced from hiPSCs via modulation of Wnt signaling followed by glucose deprivation purification. The structure, function, subpopulation composition, and tumorigenic risk of hiPSC-CMs were evaluated by single-cell RNA sequencing (scRNAseq), whole exome sequencing (WES), and integrated molecular biology, cell biology, electrophysiology, and/or animal experiments. Results: The high purity of hiPSC-CMs, determined by flow cytometry analysis, was generated. ScRNAseq analysis of differentiation day (D) 25 hiPSC-CMs did not identify the transcripts representative of undifferentiated hiPSCs. WES analysis showed a few newly acquired confidently identified mutations and no mutations in tumor susceptibility genes. Further, no tumor formation was observed after transplanting hiPSC-CMs into NOD-SCID mice for 3 months. Moreover, D25 hiPSC-CMs were composed of subtypes of ventricular-like cells (23.19%) and atrial-like cells (66.45%) in different cell cycle stages or mature levels, based on the scRNAseq analysis. Furthermore, a subpopulation of more mature ventricular cells (3.21%) was identified, which displayed significantly up-regulated signaling pathways related to myocardial contraction and action potentials. Additionally, a subpopulation of cardiomyocytes in an early differentiation stage (3.44%) experiencing nutrient stress-induced injury and heading toward apoptosis was observed. Conclusions: This study confirmed the biological safety of hiPSC-CMs and described the composition and expression profile of cardiac subtypes in hiPSC-CMs which provide standards for quality control and theoretical supports for the translational applications of hiPSC-CMs.

Basic knowledge for counseling patients undergoing risk-reducing salpingo-oophorectomy.

Significant progress has been made in the molecular diagnosis of cancer. It provides personalized medicine, including cancer diagnosis, prognosis, targeted therapy, and risk detection. These advances allow physicians to identify patients at risk for cancer before it develops and offer them an opportunity to prevent its development. Mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and 2) are one of the most well-known cancer-related gene mutations since actor Angelina Jolie shared her experience with genetic mutations and risk-reducing surgery in the media. In Korea, tests for germline BRCA1/2 mutations have been covered by insurance since May 2012 and the number of carriers of BRCA1/2 mutations has continued to increase over the past decade. Most carriers of BRCA1/2 mutations consider risk-reducing salpingo-oophorectomy (RRSO) resulting in early menopause and want to know the lifetime risks and benefits of RRSO. However, despite the increasing number of carriers of BRCA1/2 mutations, the counseling and management of patients requiring RRSO varies among physicians. This article provides basic knowledge on RRSO to help physicians comprehensively assess its risks and benefits and manage at-risk women.

Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients.

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored. To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes. In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis. In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

Abstract PO4-08-02: Genetic testing among patients with triple-negative breast cancer at a single health system: a quality improvement project

Abstract Background: Breast cancer is the most common type and the second leading cause of cancer-related deaths in women. Approximately 15-20% of patients have triple-negative breast cancer (TNBC) at diagnosis. TNBC is aggressive, difficult to treat, prone to relapse, and associated with an increased mortality rate. The incidence of BRCA1/2 mutation is about 20% in patients with TNBC (Hartman et al. 2012). Despite the high prevalence of germline mutations in cancer susceptibility genes among TNBC patients, many do not received genetic counseling (GC) or genetic testing (GT). National Comprehensive Cancer Network (NCCN) guidelines now recommend GT for all patients with TNBC, regardless of age, especially after the approval of Poly Adenosine diphosphate Ribose Polymerase (PARP) inhibitors for targeted therapy against BRCA1/2 mutations. The aim of this quality improvement (QI) project was to identify patients with TNBC who did not receive GT and design an intervention to understand potential barriers to receiving GC and GT. Methods: We implemented a QI project to identify previously diagnosed adult patients with TNBC (18 years and older) of any stage (early or advanced/metastatic) without prior GT or family history of genetic disorders with active follow-up at the Henry Ford health breast cancer clinic. Eligible patients diagnosed between January 2015 and January 2020 from the Syapse Learning Health Network database were included. Baseline information as well as additional data including demographics, breast cancer treatment details, and whether GT and/or GC was offered or not was obtained through electronic health record review after institutional review board committee approval. Bi-monthly meetings were held amongst breast cancer providers, genetic counselors, and nurse navigators to develop an intervention to contact the patients who did not undergo GT and/or GC. After obtaining the list of patients who did not undergo GT and/or GC despite meeting eligibility criteria, they were contacted by their primary breast cancer providers via telephone regarding their willingness to obtain GT and/or GC at this time and participate in a questionnaire-based interview to understand barriers towards the same. Results: In the 5 years, a total of 123 patients were noted to have been diagnosed with triple-negative breast cancer. Of these, 93 patients were actively being followed at the Henry Ford breast clinic at the time of the QI project. 2 of the 9 patients who underwent GT and GC were positive for BRCA1/2 mutation. Of the remaining 83 patients that did not receive GC or GT, 65 (78.3%) had no clear reason explained in the chart, 27 patients (32.5%) chose not to get tested, 23 (27.7%) were not deemed to be eligible upon initial assessment and 4 (4.8%) had pending orders placed by breast surgeons upon initial diagnosis. Unfortunately, 29 of these 83 patients were noted to have been deceased when the intervention was being designed. Remaining 54 patients were contacted by their primary breast cancer oncologists to determine their willingness in participating in the questionnaire-based interview. Conclusion: Based on the results of our QI project, we have now developed a process to contact the identified patients and renew the offer for GT and GC as well as participation in a questionnaire-based interview to understand the potential barriers to testing. We also plan to improve physician education and awareness by conducting mini sessions during our annual symposium meetings as well as grand rounds and develop a protocol for ordering GT and GC in patients with TNBC at our institution. Citation Format: Manasi Godbole, Mary Nyhuis, Travis Washburn, Joann Hirth, Haythem Ali. Genetic testing among patients with triple-negative breast cancer at a single health system: a quality improvement project [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 PO4-08-02.

Abstract 7334: Germline mutations in cancer susceptibility genes in patients with mucosal melanoma

Abstract Background: Mucosal melanoma (MM) is the rarest subtype of melanoma with markedly worse outcomes compared to cutaneous melanoma (CM). Unlike CM which is driven by somatic mutations due to UV exposure, risk factors for MM are less defined. While germline mutations in cancer susceptibility genes are well-studied in CM, they are less understood in MM. Herein, we aimed to identify the prevalence of germline mutations in cancer susceptibility genes in a large MM cohort. Methods: A cohort of 247 MM patients (pts) from MD Anderson Cancer Center with available blood for germline sequencing was identified. Pt characteristics were reflective of U.S. MM population with median age of 63, 60% females and 84.6% white. Clinicodemographic features of pts including tumor site, key somatic mutations (BRAF, NRAS, KIT) and personal history of other malignancies were abstracted, and their frequencies were compared in pts with and w/o germline mutation. Frequency of MITF and CHEK2 alleles were compared to expected population control rate based on TOPMED by Fisher’s exact test. Results: Among 247 pts, 10.9% had germline mutations, primarily in MITF (c.G952A:p.E318K) (2.4%) and CHEK2 (c.1100delC:p.T367fs) (1.6%) at OR of 13.9 (95%CI 5.0, 30.9) and 16.4 (4.4, 42.9) compared to population control rate (Table 1). MM sites of origin were gastrointestinal (36%), genitourinary (34%) and head &amp; neck (30%). In terms of somatic mutations, KIT (26%) was most common, followed by NRAS (15%), non-V600E BRAF (6.5%) and BRAF V600E (2.4%). These variables did not differ between those with and w/o germline mutation. Pts with germline mutation had a higher incidence of non-melanoma malignancies (48% vs 29%; p=0.044). Table 1. Summary of identified germline mutations in the mucosal melanoma cohort. Germline mutation Protein MITF (N= 6) p.E318K CHEK2 (N=4) p.T367fs MUYTH p.G368D ATM splice ATM p.L263fs ATM p.R1875X ATM p.L1327X ATM p.A2067D ATM p.R2034X BRCA2 p.A1689fs CHEK2 p.S400T ERCC3 p.R109X MITF p.C29Y NF1 p.L1183R PALB2 p.V221X POLE p.D287E TP53 p.R306X TP53 p.V73Wfs*50 TSC1 p.Q844X Conclusions: This study reports a high prevalence of germline cancer susceptibility mutations in the largest cohort of MM to date, including mutations which are actionable. There is overlap with known MITF risk alleles for CM. We are currently performing a GWAS to comprehensively understand the genetic architecture of risk in MM. Citation Format: Afsaneh Amouzegar, Xiaogang Wu, James Long, Sabitha Prabhakaran, Latasha Little, Curtis Gumbs, Jared Malke, Julie Simon, Jianhua Zhang, Jennifer Wargo, Paul Scheet, Justin W. Wong, Priyadharsini Nagarajan, Jennifer L. McQuade, Andrew Futreal. Germline mutations in cancer susceptibility genes in patients with mucosal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7334.

Identification of pancreatic cancer risk factors from clinical notes using natural language processing

ObjectivesScreening for pancreatic ductal adenocarcinoma (PDAC) is considered in high-risk individuals (HRIs) with established PDAC risk factors, such as family history and germline mutations in PDAC susceptibility genes. Accurate assessment of risk factor status is provider knowledge-dependent and requires extensive manual chart review by experts. Natural Language Processing (NLP) has shown promise in automated data extraction from the electronic health record (EHR). We aimed to use NLP for automated extraction of PDAC risk factors from unstructured clinical notes in the EHR. MethodsWe first developed rule-based NLP algorithms to extract PDAC risk factors at the document-level, using an annotated corpus of 2091 clinical notes. Next, we further improved the NLP algorithms using a cohort of 1138 patients through patient-level training, validation, and testing, with comparison against a pre-specified reference standard. To minimize false-negative results we prioritized algorithm recall. ResultsIn the test set (n = 807), the NLP algorithms achieved a recall of 0.933, precision of 0.790, and F1-score of 0.856 for family history of PDAC. For germline genetic mutations, the algorithm had a high recall of 0.851, while precision and F1-score were lower at 0.350 and 0.496 respectively. Most false positives for germline mutations resulted from erroneous recognition of tissue mutations. ConclusionsRule-based NLP algorithms applied to unstructured clinical notes are highly sensitive for automated identification of PDAC risk factors. Further validation in a large primary-care patient population is warranted to assess real-world utility in identifying HRIs for pancreatic cancer screening.

Abstract 1723 Differences in barriers to immortalization in normal breast epithelial cells from donors with and without mutations in breast cancer susceptibility genes

Abstract 1723 Differences in barriers to immortalization in normal breast epithelial cells from donors with and without mutations in breast cancer susceptibility genes

A rare germline BMP15 missense mutation causes hereditary ovarian immature teratoma in human

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer

BackgroundIdentifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC.Materials and methodsIn this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness.ResultsAge at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702—0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755—0.894] versus 0.659 [0.563—0.755], p = 0.007).ConclusionThe nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

Abstract TP233: Cerebral Microbleeds Are More Frequent With BRCA Mutations: A Single-Center Retrospective Study

Introduction: Breast cancer susceptibility gene (BRCA) mutations are well-known causes of systemic cancers. We have previously identified that those with BRCA mutations have a higher likelihood of cerebral microbleeds (CMBs) on brain MRI compared to BRCA wildtype. We aimed to confirm our prior findings in a subsequent cohort. Methods: We performed a single-center retrospective review of all individuals with a confirmed diagnosis of BRCA 1 or 2 mutation and a standard-of-care brain MRI. All individuals were ≥ 18 years old, without intracranial radiation, cerebral metastases, or other cerebral processes which may impact interpretation. Our comparative cohort were individuals with breast cancer who have a genetically confirmed BRCA wildtype status. The primary outcome was the presence of CMBs, defined by consensus criteria. Standard descriptive techniques were used. Likelihood ratios were calculated by binary logistic regression and adjusted for significant variables. Results: We identified 49 individuals who met inclusion criteria: 15 with BRCA mutation and 34 with BRCA wildtype. Only one patient was with aspirin use in the BRCA mutation cohort. All cancers were of breast origin with 4 BRCA mutations patients with cancer staging ≥ 3 compared with 14 in the BRCA wildtype cohort. Chemotherapy rates did not differ. Patients with BRCA were younger, less often with hyperlipidemia, and more commonly had CMBs, Table 1. The presence of BRCA mutation trended towards higher odds of having a CMB (OR 5.8, 95%CI 0.93 - 36.16, p = 0.059) after adjustment for age and hyperlipidemia. Conclusion: We found that CMBs were more common in the BRCA mutation cohort, with a trend towards a 5-fold higher likelihood in the regression analysis. While underpowered, our findings support prior data highlighting this association. Further studies with larger sample sizes are warranted.

Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations

Germline mutations in Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) cause breast, ovarian, and other cancers, and the chemotherapeutic drug doxorubicin (Dox) is widely used to treat these cancers. However, Dox use is limited by the latent induction of severe cardiotoxicity known as Dox-induced cardiomyopathy, for which there are no specific treatments currently available. Dox is administered into the systemic circulation, where it readily translocates into sub-cellular compartments and disrupts the integrity of DNA. Accumulating evidence indicates that oxidative stress, DNA damage, inflammation, and apoptosis all play a central role in Dox-induced cardiomyopathy. The BRCA1 and BRCA2 proteins are distinct as they perform crucial yet separate roles in the homologous recombination repair of DNA double-strand breaks, thereby maintaining genomic integrity. Additionally, both BRCA1 and BRCA2 mitigate oxidative stress and apoptosis in both cardiomyocytes and endothelial cells. Accordingly, BRCA1 and BRCA2 are essential regulators of pathways that are central to the development of cardiomyopathy induced by Doxorubicin. Despite extensive investigations, there exists a gap in knowledge about the role of BRCA1 and BRCA2 in Doxorubicin-induced cardiomyopathy. Here, we review the previous findings and associations about the expected role and associated mechanisms of BRCA1 and 2 in Dox-induced cardiomyopathy and future perspectives.

Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.

Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

SAT332 Genetic Characterization Of A Case of Pheochromocytoma In A Pulmonary Transplant Patient

Abstract Disclosure: F. Perreault: None. S. Parisien-Lasalle: None. J. Morisset: None. C. Poirier: None. C. Beauregard: None. R. Agnès: None. P. Ferraro: None. I. Bourdeau: None. Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors arising from the chromaffin cells. Approximately 40% of PPGL patients carry germline mutations in susceptibility genes, including pseudohypoxic related SDHx and VHL genes. An association was described between hypoxemia and PPGLs, notably in higher altitude exposition and cyanotic congenital heart disease. In the latter, a chronic hypoxemic state can lead to gain of function somatic mutations in the EPAS1 gene that encodes for hypoxia-inducible factor 2-alpha (HIF-2) (1). Objective: To describe a rare case of PHEO in a pulmonary transplant patient and characterize the genetic background of the tumor. Clinical Case: A 66 year-old man underwent an unilateral lung transplant at the age of 47 for chronic obstructive pulmonary disease associated with alpha-1 antitrypsin deficiency. He required home oxygen therapy for 3 years prior to transplant and was known for new onset diabetes after transplant, chronic kidney disease, hypertension and paroxysmal atrial tachycardia. His family history was non-contributing. Nineteen years after transplant, a thoracic CT-scan showed a 6.1 cm x 3.9 cm right adrenal mass (HU of 7). Retrospectively, the mass had been present for the last seven years, and increased progressively in size. Diagnosis of PHEO was confirmed by the 24-h urinary catecholamines (norepinephrine 713 nmol/d (N&amp;lt; 650), epinephrine 588 nmol/d (N &amp;lt; 145), normetanephrines 900 nmol/d (N &amp;lt; 600) and metanephrines 1191 nmol/d (N &amp;lt; 370)). Chromogranin A was elevated (3297 ng/mL (N &amp;lt; 104)). The adrenal mass showed no uptake at 18F-FDG PET/CT imaging but fixation at MIBG scintigraphy. The patient received alpha blockers and underwent a laparoscopic right adrenalectomy. The pathology report confirmed a PHEO with a PASS score of 8 to 10. Eighteen months following the surgery, the patient showed no signs of biochemical or radiological recurrence. Genetic studies: 1) Germline PPGL multigene panel: After consent, the patient underwent a panel of 14 susceptibility genes for PPGLs (INVITAE, CA, USA) that revealed no pathogenic variants. 2) Somatic genetic analysis for EPAS1 gene: PHEO DNA was extracted and exons 9, 12 and 16 of the EPAS1 gene were studied by Sanger Sequencing. No pathogenic variants were identified.Conclusion: We report a rare case of PHEO in a pulmonary transplant patient. Our genetic analyses demonstrated the absence of a pathogenic germline variant in known susceptibility PPGL genes and no somatic mutations in the EPAS1 gene. Further work is needed to better understand the genetic and molecular events leading to PHEO in this specific case and determine its possible relationship with hypoxemia. (1) Vaidya A, Flores SK, Cheng Z-M, Nicolas M, Deng Y, Opotowsky AR, et al. EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease. New England Journal of Medicine. 2018;378(13):1259-61. Presentation: Saturday, June 17, 2023