Prevalence Of Germline Mutations Research Articles

Prevalence of Genetic Mutations in Patients with Metastatic Prostate Cancer in a Cohort of Mexican Patients

Background: Prostate cancer is a malignant neoplasm of the male genitourinary system with the highest incidence worldwide. Susceptibility genes related to aggressiveness and prognosis, such as BRCA1/2, ATM, PTEN, have been identified. Currently, reports related to germline mutations in patients with prostate cancer in Latin American populations are very limited or absent. In the Mexican population, reports are also limited, especially in the context of metastatic prostate cancer. Determining the prevalence of these mutations is relevant to predict the potential aggressiveness of tumors and allow the use of targeted therapies, such as PARPi inhibitors. Objective: Determine the prevalence of germline mutations in patients with metastatic prostate cancer and establish their clinical characteristics at diagnosis. Material and Methods: Sixty-nine patients with metastatic PCa underwent testing and genetic analysis using the Comprehensive Multi-Cancer Hereditary Cancer Panel. The prevalence of germline mutations was assessed, and the cohort was divided into two groups for the evaluation and analysis of clinical characteristics between the mutated and non-mutated populations. Results: We identified mutations in 15 out of 69 patients (21.73%), while 54 patients (78.26%) had no mutations. Pathogenic mutations were observed in 15.9% of patients, Variants of Uncertain Significance (VUS) in 34.78%, and 5.79% had both. The most frequent mutations included ATM (11.54%), BRCA1 (11.54%), BRCA2 (7.69%), FANCA (7.69%), and FANCM (7.69%). No statistically significant differences were found in PSA levels, age at diagnosis, and resistance to castration between the two groups. Conclusions: Our study unveiled a mutation rate of 21.73%, marked by a significant prevalence of ATM, FANCA, FANCM, and Variants of Uncertain Significance (VUS). This pattern deviates from findings in other series, underscoring the necessity for improved access to clinical genetic testing in our population.

Mutations and mortality in very young patients with breast cancer.

e13157 Background: Breast cancer diagnoses in young women have increased over the last 10 years. Despite decreasing mortality rates for breast cancer, disparities continue to exist for specific populations including Black women and premenopausal women. Recent studies observe a 41% increased death rate in Black women compared to White women, and a two-fold increased mortality in women younger than 50 years. Many biological and societal factors can affect breast cancer mortality. We sought to evaluate the relationship between germline mutations (GM), breast cancer subtype, and mortality based on race in a unique, young breast cancer patient population. Methods: We assembled a 10-year retrospective chart review (2012 to 2022) of 773 women diagnosed with breast cancer under the age of 40 in a regional health network. Data was collected from electronic medical records. Associations were assessed using the chi-square test using SAS version 9.4. Results: Out of the 773 patient information collected, 60% of patients were White, 36% Black, and 3% Other. A total of 675 patients had genetic results and 124 patients with documented GM. Of patients with GM, 48 were Black and 74 were White. 13 patients with germline mutations had documented deaths. There was no statistical link between germline mutations and mortality. Of the 13 patients, 4 (30%) were Black and 9 (70%) were White. There was no statistical difference amongst area deprivation index (ADI) quintiles for mortality in patients with GM. Of the 675 patients with genetics data, 72 patients without GM died which includes 31 Black patients, 38 White patients, 3 Other. Based on our data, there is a higher prevalence of germline mutations (60%) in White patients over Black patients and a descriptive predominance of mortality despite absence of statistical significance. More patients who resided in areas of higher ADI (2-4) with GM died than in areas of lower ADI. Conclusions: Our data demonstrates a descriptive prevalence in mortality among young White patients compared to young Black patients. Across the USA, the Black population is 13% and in Louisiana, that population is 33%. Given that our cohort population was 36% Black, it is noteworthy that we were unable to demonstrate a statistical mortality predominance among these young patients. [Table: see text]

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients [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 PO1-09-02.

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.

Germline Genetic Mutations in Adult Patients with Sarcoma: Insight into the Middle East Genetic Landscape.

Data on germline mutations in soft tissue and bone sarcomas are scarce. We sought to identify the prevalence of germline mutations in adult sarcoma patients treated at a tertiary cancer center. Newly diagnosed patients were offered germline genetic testing via an 84-gene panel. The prevalence of pathogenic germline variants (PGVs) and their association with disease-, and patient- related factors are reported. A total of 87 patients were enrolled, the median age was 48 (19-78) years, and 47 (54%) were females. Gastrointestinal stromal tumors (n = 12, 13.8%), liposarcoma (n = 10, 11.5%), and Ewing sarcoma (n = 10, 11.5%) were the main subtypes. A total of 20 PGVs were detected in 18 (20.7%) patients. Variants of uncertain significance, in the absence of PGVs, were detected in 40 (45.9%) patients. Young age (p = 0.031), presence of a second primary cancer (p = 0.019), and female gender (p = 0.042) were correlated with the presence of PGVs. All identified PGVs have potential clinical actionability and cascade testing, and eight (44.44%) suggested eligibility for a targeted therapy. Almost one in five adult patients with soft tissue and bone sarcomas harbor pathogenic or likely pathogenic variants. Many of these variants are potentially actionable, and almost all have implications on cancer screening and family counselling. In this cohort from the Middle East, younger age, presence of a second primary tumor, and female gender were significantly associated with higher PGVs rates. Larger studies able to correlate treatment outcomes with genetic variants are highly needed.

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System

BackgroundGermline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil.MethodsA cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes.ResultsThe prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time.ConclusionOne in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

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 & 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.

Prevalence and spectrum of germline BRCA1 and BRCA2 in a cohort of ovarian cancer patients from the Salento peninsula (Southern Italy): a matter of preventive health.

The aim of this exploratory, descriptive study was to characterize the deleterious BRCA1 and BRCA2 variants evaluated by genetic testing in a group of Ovarian cancer patients living in the Salento peninsula (Southern Italy). From June 2014 to July 2023, patients with histologically confirmed high-grade serous carcinoma, fallopian tube, or primary peritoneal cancer who were referred to Lecce Familial Cancer Clinic were considered. BRCA-mutation genetic testing was performed on these patients. Socio-demographic data and cancer epidemiology were assessed, and Next Generation Sequencing and Sanger DNA sequencing were performed. The median age at the diagnosis of 332 ovarian cancer patients collected was 57 years. The pedigree analyses showed that 28.6% had familial cases and 39.7% had sporadic cases. Of the 319 patients submitted to genetic testing, 29.8% were carriers of BRCA1/2 mutation, 75.8% at BRCA1 and 24.2% at BRCA2 gene. Of the 21 BRCA1 mutations, the variant c.5266dupC was the most frequent alteration (28.4%). With respect to BRCA2, 13 mutations were found and the variant c.9676delT was the most frequently recorded (6.3%). This study reveals that the prevalence of germline mutations in the BRCA1 and BRCA2 genes was higher than reported by other studies. A broader understanding of the prevalence and role of BRCA mutations in development, response to treatment, and prognosis represents an exciting and developing area of ovarian cancer treatment and prevention.

Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).

193 Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]

Genetic predisposition to differentiated thyroid cancer in the Polish population.

Genome sequencing technologies reveal molecular mechanisms of differentiated thyroid cancer (DTC). Unlike somatic mutation analysis from thyroidectomy samples, germline mutations showing genetic susceptibility to DTC are less understood. The study aimed to assess the prevalence of germline mutations predisposing to DTC in a cohort of Polish individuals based on their whole genome sequencing data. We analyzed sequencing data from 1076 unrelated individuals totaling over 1018 billion read pairs and yielding an average 35.26 × read depth per genome, released openly for academic and clinical research as the Thousand Polish Genomes database (https://1000polishgenomes.com). The list of genes chosen for further analysis was based on the review of previous studies. The cohort contained 104 variants located within the coding and noncoding DNA sequences of 90 genes selected by ClinVar classification as pathogenic and potentially pathogenic. The frequency of variants in the Polish cohort was compared with the frequency estimated for the non‑Finnish European population obtained from the gnomAD database (gnomad.broadinstitute.org). Significant differences in variant frequency were found for the APC, ARSB, ATM, BRCA1, CHEK2, DICER1, GPD1L, INSR, KCNJ10, MYH9, PALB2, PLCB1, PLEKHG5, PTEN, RET, SEC23B, SERPINA1, SLC26A4, SMAD3, STK11, TERT, TOE1, and WRN genes. Even though the Polish population is genetically similar to the other European populations, there are significant differences in variant frequencies contributing to the disease development and progression, such as those in the RET, CHEK2, BRCA1, SLC26A4, or TERT genes. Further studies are needed to identify genomic variants associated directly with DTC.

Genetic testing in prolactinomas: a cohort study.

Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on hereditary predisposition to prolactinoma. We studied the prevalence of germline mutations in a large cohort of patients with isolated prolactinomas. A retrospective study was performed combining genetic and clinical data from patients referred for genetic testing of MEN1, AIP, and CDKN1B between 2003 and 2020. SF3B1 was Sanger sequenced in genetically negative patients. About 506 patients with a prolactinoma were included: 80 with microprolactinoma (15.9%), 378 with macroprolactinoma (74.7%), 48 unknown; 49/506 in a familial context (9.7%). Among these, 14 (2.8%) had a (likely) pathogenic variant (LPV) in MEN1 or AIP, and none in CDKN1B. All positive patients had developed a macroprolactinoma before age 30. The prevalence of germline mutations in patients with isolated macroprolactinoma under 30 was 4% (11/258) in a sporadic context and 15% (3/20) in a familial context. Prevalence in sporadic cases younger than 18 was 15% in men (5/33) and 7% in women (4/57). No R625H SF3B1 germline mutation was identified in 264 patients with macroprolactinomas. We did not identify any LPVs in patients over 30 years of age, either in a familial or in a sporadic context, and in a sporadic context in our series or the literature. Special attention should be paid to young patients and to familial context.

Prevalence of germline mutations in women with breast and/or ovarian cancer in a tertiary care center in Pune, India

In India, the incidence of breast cancer accounted for 1,78,361 cases, whereas ovarian cancer accounts for 45,701 cases, according to Globocan Report 2020. These cancers are known to have a hereditary basis, and >10% of them are associated with pathogenic BRCA1 and BRCA2 mutations. The prevalence of BRCA1 and BRCA2 varies across various Indian studies and is reported to be 2.9–28%. However, gene mutations other than BRCA1 and BRCA2 which are shown to increase the risk of hereditary breast and ovarian cancer (HBOC) are underreported. Objectives: The objective of this study was to estimate the prevalence of deleterious germline mutations among women with breast and/or ovarian cancer. Material and Methods: A cross-sectional study was conducted in the department of oncology at a super specialty hospital. Patients were enrolled based on the current National Comprehensive Cancer Network guidelines for genetic risk and evaluation of HBOC. Demographic and clinical information was extracted from the electronic medical records of the hospitals from 2018 to 2021. Next-generation sequencing (NGS) was performed on the extracted DNA using a custom capture kit and classified based on the American College of Medical Genetics. Results: A total of 94 patients suspected of having HBOC were examined for deleterious germline mutations. The median age of the patient was 46 years (range: 38–57 years). Breast and ovarian cancer patients constituted 64.9% and 35.1%, respectively. The overall mutation detection rate was 25.5%. The positive mutation detection rate was 26.2% and 24.2% in breast and ovarian cancer, respectively, whereas the variant of uncertain significance rate was 18.03% and 24.2%, respectively. Among the pathogenic mutations, BRCA1 was the most common mutation in women with breast cancer (81.3%). In ovarian cancer, it was 50%. BRCA2 mutation was more prevalent in ovarian cancer (50%). Conclusion: Our study reports a higher prevalence of germline BRCA1 and BRCA2 mutations in breast and ovarian cancer as compared to other studies. Genetic testing can be offered to high-risk women regardless of family history. This will be useful during diagnosis and help physicians in planning subsequent treatment.

BRCA mutations in triple negative breast cancer patients in Guatemala: A descriptive study.

e22543 Background: In Guatemala, breast cancer is the most common malignancy among women, the habitants in the country are characterized by being of different ethnic groups and little is understood about the prevalence of germline mutations and their influence in the prognosis and diagnosis of triple negative breast cancer patients, reason why the aim of our study is to determine the prevalence of BRCA1 and BRCA2 germline mutations among this population. Methods: Forty-five patients with confirmed biopsy of triple negative breast cancer by immunohistochemistry treated at Liga Nacional Contra el Cáncer-INCAN Guatemala in 2022 were enrolled in the study. Triple negativity was defined as < 1% estrogen, progesterone and HER2 staining by immunohistochemistry or not amplified by fluorescence in situ hybridization in those with HER2 borderline result. After consent, patients had next generation sequencing and multiplex ligation-dependent probe amplification for BRCA1 and BRCA2 genes. From medical records, we obtained: demographic, clinico-pathological and treatment data. Median was calculated for age, while frequencies and percentages were computed for the categorical variables. Results: The study identified 19 patients with a BRCA1 or BRCA2 germline mutations (42.22%). The median age at cancer diagnosis was 39 vs. 49 years old compared to patients with lack of mutations of the genes analyzed. The majority harboring a mutation (36.84%) were from the countryside, especially the regions IV and V (southeast and central). Among all groups, (66.67%) were diagnosed with locally advanced disease and initially treated with neoadjuvant chemotherapy. According to our findings, the most prevalent mutations were located in the BRCA1 gene (47.37%), with BRCA1 c.212+1G > A and BRCA2 c.2806_2809del being the most frequent variants (36.84%). Conclusions: Triple negative breast cancer patients in Guatemala have higher prevalence of BRCA1 and BRCA2 mutations than reported among other populations, longer follow up of this study is expected to confirm the results and further understand how the presence of mutations could affect the response to treatment of the patients, their prognosis and the impact in their families. [Table: see text]

Genomic landscapes of early-onset versus average-onset colorectal cancer populations.

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]

Genetic testing outcomes and pathogenic germline mutation prevalence in renal cell carcinoma.

10601 Background: Germline mutations have been observed in renal cell carcinoma (RCC) with varying frequencies reported from 5% to 18% of patients. Due to the prevalence of germline mutations, current guidelines by the National Comprehensive Cancer Network (NCCN) recommend genetic testing for patients with RCC and high-risk factors such as young age, bilateral or multifocal tumors, family history of RCC, as well as certain RCC histologies. However, the germline mutational landscape in RCC has not been fully characterized. Here, we report the genetic testing results and clinicopathologic factors of patients with RCC who were referred for germline testing. Methods: All patients with a diagnosis code of kidney cancer and referred to the Cancer Genetics clinic at the University of Michigan between 2004 and 2022 were identified. Patients were excluded if they had erroneous RCC diagnosis codes, no history of RCC diagnosis, known familial/hereditary mutation or syndrome, or did not undergo germline testing. Genetic testing outcomes, germline mutation frequency, and clinical factors were obtained through chart review and analyzed using descriptive statistics. Results: A total of 322 patients with a history of RCC and referred for genetic testing were identified. The median age at diagnosis in all patients was 47 (interquartile range: 38-58). Males accounted for 56.8% of the cohort. Most patients (62.4%) had clear cell histology at initial diagnosis, whereas 30.7% had non-clear cell histology. The majority of patients (61.5%) were diagnosed at stage 1. Bilateral and multifocal tumors at diagnosis accounted for 18.9% and 12.7%, respectively. Pathogenic or likely pathogenic variants (P/LP) were identified in 43 patients (13.4%); 225 patients had negative germline testing (69.9%); 54 patients (16.8%) had a variant of unknown significance (VUS). The most frequently mutated RCC-associated genes were FLCN (n=10, 3.1%), SDHA/B/D (n=7, 2.2%), VHL (n=4, 1.2%), MLH1 (n=3, 0.9%), and FH (n=2, 0.6%). Common mutations in other cancer-related genes were CHEK2 (n=4, 1.2%), ATM (n=2, 0.6%), and RAD50 (n=2, 0.6%). Most patients (81.4%) with a P/LP test result had at least 1 of the following: diagnosis age ≤ 46 years, bilateral or multifocal tumors, or at least 1 first-degree relative with RCC. Out of the patients with a P/LP result, 18 patients (39.1%) had a potentially actionable mutation. Conclusions: Among patients with RCC who were unselected for a known familial/hereditary predisposition, P/LP variants were present in 13.4% which is consistent with previous studies. The prevalence of FLCN mutations was higher in our cohort (3.1%) compared to prior observations. Most patients with a P/LP variant met the NCCN criteria for genetic testing. Future studies should optimize the current genetic testing criteria to identify a broader group of patients who may have germline mutations given potential cascade testing and therapeutic implications.

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis

we enrolled for NGS with an Illumina TrueSight Cancer panel comprising 19 CPGs and 113 consecutive subjects referred to cancer genetic clinics for metastatic PDAC, early onset PDAC, suspected hereditary syndrome, or positive family history. Overall, 23 (20.1%) subjects were carriers of 24 pathogenetic variants (PVs). We found 9 variants in BRCA2 (37.5%), 6 in CDKN2A (25%), 3 in ATM (12.5%), 2 in BRCA1 (8.3%), 1 in CHEK2 (4.1%), 1 in PALB2 (4.1%), 1 in MITF (4.1%), and 1 in FANCM (4.1%). A double PV (BRCA1 plus BRCA2) was found in 1 subject. We observed a nearly 30% (16/55) mutational rate in the subgroup of subjects tested for the suspected syndromes (PDAC and other synchronous or metachronous tumors or an indicative family history), and the frequency was significantly higher than that in patients with only metastatic PDAC (p = 0.05). In our cohort, 39 variants of unknown significance (VUS) were identified, most of which (16/39, 41%) in genes belonging to the Lynch syndrome spectrum. A clinically relevant proportion of pancreatic cancer is associated with mutations in known predisposition genes. Guidelines instructing on an adequate selection for accessing genetic testing are eagerly needed. The heterogeneity of mutations identified in this study reinforces the value of using a multiple-gene panel in pancreatic cancer.

SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update.

Loss of function of the succinate dehydrogenase complex characterizes 20-40% of all KIT/PDGFRA-negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB, SDHC, and SDHD mutations in GIST occur in only 20-30% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives.

Prevalence of HRR gene mutations in patients with metastatic castration-resistant prostate cancer: Germline results from the Latin-American observational study PROSPECT.

226 Background: Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, and 20% to 30% of patients harbor alterations in homologous recombination repair (HRR) genes. However, data regarding the genetic profile of mCRPC in Latin American populations are scarce. This study determined the prevalence of HRR gene mutations in Latin American patients with mCRPC to better understand this population and guide future policies. The interim analysis herein reports results focused on germline alterations only. Methods: PROSPECT (NCT04962880) is a cross-sectional, non-interventional, multicenter study. Patients were adults (≥18 years) diagnosed with mCRPC from November 2020 to October 2021 at centers in Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, and Peru. Diagnoses were confirmed by laboratory testing (PSA and/or testosterone levels) or imaging (X-ray, CT, MRI, or PET scan). All patients provided written informed consent. Blood samples were assayed to determine the prevalence of germline mutations in HRR genes in the participating countries using the AmoyDx HANDLE HRR Next Generation Sequence 32 genes Panel (AmoyDx, Xiamen, China). Results: Overall, 388 participants with a median age of 70 years (range: 49‒89) were included in this study, including 184 Hispanic (47.4%), 101 White (26%), 40 Mestizo (10.3%), 11 African American (2.8%), 2 Asian (0.5%), and 50 “other” (12.9%) patients. Over a third of them (n=151, 38.9%) had a family history of cancer. Median time since prostate cancer diagnosis was 3 years (range: 0‒23) and 2 years (range: 0‒22) since mCRPC diagnosis. Metastases were most frequently localized to the bones (59.6%). The patients’ ECOG status was either 0 (173/365; 47.4%) or 1 (192/365; 52.6%). Among the 167 patients that received treatment, most received androgen deprivation therapy alone (43.7%) or with radiotherapy (21.6%). Overall, 25/381 patients (6.56%) had germline HRR mutations. The 5 most frequently mutated HRR genes were BRCA2 (16%), ATM (12%), CHEK2 (12%), BRIP1 (8%) and HOXB13 (8%). Conclusions: The prevalence of germline HRR mutations found in this multinational Latin American population was lower than expected compared to previously reported rates ranging from 8% to 12% from other countries. Additionally, the most frequently mutated HRR genes differed from those from major trials including PROfound (NCT02987543). Clinical trial information: NCT04962880 . [Table: see text]

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma.

Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance. Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ2) was used to analyze relationship between clinicopathologic parameters and germline mutations. A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations. To our knowledge, this is the first report of pathogenic germline mutations in the FANCI and FANCM genes and heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.

Initial clinical results of the first commercial clinical blood test dedicated to the early detection of pancreatic ductal adenocarcinoma (PDAC).

e16258 Background: The IMMray® PanCan-d blood test for early detection of PDAC has been commercially available in 45 U.S. states since the laboratory’s licensure in August 2021. This is the first clinically-available blood test dedicated to the early detection of PDAC, combining an 8-plex biomarker signature with CA19-9 in a proprietary algorithm. Here we report the initial results of this assay. Methods: All orders received and results reported were reviewed for the IMMray PanCan-d test between August 4, 2021 and February 11, 2022. Serum specimens were processed at the Immunovia, Inc. laboratory in Marlborough, Massachusetts. Demographic information of individuals undergoing testing is based on the completed test requisition submitted by their health care providers. All information was de-identified prior to this analysis. Results: The median age of those tested was 59 years and 46% were male. 76% of patients were referred because of a history of familial pancreatic cancer. Germline mutation prevalence is reported in the table below. 12% of patients had IPMNs or mucinous cystic neoplasms, 2% had chronic pancreatitis and 3% had new onset Diabetes Mellitus. Table. Demographics of Individuals Tested with the IMMray PanCan-d test 80.5% of IMMray PanCan-d results were negative, 1.1% were high-risk signature present, and 11.5% were borderline. These results are fully consistent with validation studies for this assay in high-risk surveillance populations (Brand RE et al Clin Transl Gastroenterol, doi: 10.14309/ctg.0000000000000468). 6.9% of individuals tested had a CA19-9 value of less than 2.5 U/ml, which we identify as presumptively Lewis null (le/le) and CA19-9 non-secretors. Given that CA19-9 contributes significantly to calculated decision values for the IMMray PanCan-d test, individuals with a CA19-9 less than 2.5 U/ml receive a result of test not performed. Conclusions: The commercial availability of a biomarker assay for the early detection of PDAC resulted in a testing population with demographics and referral criteria similar to that of PDAC high-risk surveillance programs in the U.S. IMMray PanCan-d test results were as expected based on prior validation studies.[Table: see text]