HBOC Syndrome Research Articles

Sexual Function in Women Diagnosed with Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary breast and ovarian cancer syndrome (HBOC) predisposes women to an increased risk mainly of breast and tubo-ovarian cancer. The aim of the study is to investigate whether being diagnosed with HBOC syndrome is itself a risk factor for sexual dysfunction. An ad hoc questionnaire, including baseline demographic and clinical data, and the Sexual Function Questionnaire 28 (SFQ28) were administered to HBOC female carriers (study group) and to a control group. After propensity score matching (1:1), we enrolled 202 women, 101 in the study group and 101 in the control group. In a multivariate analysis, we finally found that menopausal status was the only risk factor for a significant low score in the domains Desire (HR 0.66; CI95% 0.47-0.93; p = 0.017), Arousal (Lubrication) (HR 0.52; CI95% 0.34-0.80; p = 0.003), Arousal (Cognitive) (HR 0.64; CI95% 0.44-0.95; p = 0.027), and Orgasm (HR 0.33; CI95% (0.16-0.70; p = 0.004), independent of risk-reducing surgery for gynecological malignancy. Psycho-oncology support is a protective factor for the Enjoyment domain (HR 1.38; CI95% 1.05-1.81; p = 0.022). HBOC syndrome itself does not affect SFQ28 domains, while menopausal status significantly influences sexual health, with potential mitigating effects of psycho-oncological support.

Abstract 6102: Clinicopathological and genetics features of endometrial cancer in Algerian women: The first nation-wide study

Abstract Background: Endometrial cancer represents the fourth common cancer in women in Algeria and the fifth cause of cancer mortality. In the present study, we aimed to determine, clinical, tumor and genetics characteristics associated with endometrial cancer in Algerian women. In addition, we screened for germline pathogenic variants in MMR genes in endometrial cancer patients with strong family history of Lynch syndrome (LS). Materials and Methods: Our study population included 273 patients diagnosed with endometrial cancer between 2010 and 2021. Data were collected from three public hospitals that covered 29 provinces among 48 in Algeria. Patient and tumor information included: age at diagnosis, menopausal status, histological type, histological grade, TNM stage, FIGO stage, tumor markers CA125, ACE, CA19-9, family history with cancer and age at menarche . MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS 2(exons 6 and 10) were screened by PCR-Sanger direct sequencing in 14 LS families . Results: The mean age at diagnosis was 58.88 years. The mean age at menarche was 13.5 years. The proportion of endometrial cancer patients with premenopausal status was 21.62%. The commonest histological type was endometrioid adenocarcinoma (66.79%) followed by clear cell carcinoma (8.10%), carcinosarcomas (3.86%), serous carcinoma (3.47%) and mucinous carcinoma (2.7%). We found that the proportion of tumors with histological grade I (34.74%), grade II (27.41%) and grade IV (21.40%) was commonest in 83.55% of the patients. Our results showed that 73.74% of the patients were diagnosed at stage I (50.19%), stage II (12.74%) and stage III (10.81%), respectively. For the FIGO staging, our results showed that 74.12% of the patients were diagnosed at stage I (52.89%), stage III (10.81%) and stage I (10.42%), respectively. 16.21%, 3.08%, 6.94% of the patients were positive for CA125, ACE and CA19-9, respectively. We noticed that 56 patients (20.43%) had a positive family history with HBOC syndrome (17), Lynch syndrome (26) and Cowden syndrome (13), respectively. We identified two distinct germline pathogenic variants in MLH1 gene in two LS families. We detected the new germline pathogenic variant MLH1 c.53_63delinsT in young patient diagnosed with endometrial cancer and colorectal cancer (CRC) at age 43y and 44 y, respectively. The rare pathogenic germline variant MLH1 c.1546C>T has been detected in young woman diagnosed with CRC at age 41y and endometrial and ovarian cancers at age 52y, respectively. Conclusions : In this first study, we reported some clinical, biological, tumor and genetics features of endometrial cancer in Algerian women. Interestingly, we noticed that the median age of diagnosis was younger that the average age in Europe and America. Genetic counseling and testing is recommended for endometrial cancer patients diagnosed before age 50 with a family history of Lynch syndrome. Citation Format: Farid Cherbal, Chiraz Mehemmai, Mouchira Saidi, Yasmine Santoudji, Djamel-Eddine Seddik, Asma-Lamia Boumehdi, Fatiha Gouaref, Kamel Bentabak, Hassen Mahfouf, Mohammed Oukkal. Clinicopathological and genetics features of endometrial cancer in Algerian women: The first nation-wide study [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 6102.

Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.

Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation. The portal was developed following the completion of 25 semistructured interviews with individuals having undergone HCS susceptibility testing at BC Cancer. Following initial development, we recruited patients and healthcare providers to provide critical feedback informing portal refinement. Quantitative feedback was summarized using descriptive statistics, and qualitative feedback was synthesized by two reviewers who engaged in iterative discussion within the research team to prioritize recommendations for integration. The patient portal includes four key components consisting of (a) targeted educational information about hereditary cancer and HBOC syndrome associated risks and testing process overview, (b) a general frequently asked questions 'FAQ' page informed by the qualitative interviews, patient partner feedback,and consultation with the HCP, (c) guidance to support familial communication including a video developed with a patient partner describing their lived experience navigating the communication processand (d) a series of lay summaries of genetic test findings to support information transfer among family members. Thirteen healthcare providers and sevenpatients participated in user testing. Domains within which participant recommendations were provided included presentation, educational contentand process clarification. This investigation demonstrates the value of continual integration of patient and provider preferences through the development of tools endeavouring to assist with complex genomics-informed decision-making. Our work aims to broaden the population-wide impact of HCS testing programs by improving communication processes between probands and their potentially affected family members. This work involved a patient partner who was actively engaged in all aspects of the research investigation including protocol development, review and editing of all study documentation (including that of the previously published qualitative investigation), interpretation of results, as well as reviewing and editing the manuscript. Patient partners and healthcare professionals were recruited as research participants to provide critical feedback on the patient portal.

Prenatal genetic counseling practices regarding recommendations for cancer genetic counseling: A retrospective chart review from two academic institutions.

Prenatal and preconception genetic counselors are trained to take patient pedigrees to evaluate for potential risks for genetic conditions, including hereditary cancer syndromes. However, little research has been published on how often prenatal/preconception genetic counselors provide recommendations for cancer genetic counseling solely based on a family history of cancer. Therefore, this study sought to (a) characterize the types of cancers recognized for a cancer genetic counseling recommendation, (b) analyze appointment indications associated with discussion documentation, and (c) investigate how often National Comprehensive Cancer Center (NCCN) genetic testing criteria for Hereditary Breast and Ovarian Cancer syndrome (HBOC) and Lynch syndrome were met and how often a recommendation for cancer genetic counseling was made. A retrospective chart review and pedigree analysis were performed for prenatal/preconception genetic counseling patients with a family history of cancer seen at two academic institutions between August 10, 2019, and December 1, 2019. In the 170 charts included, a recommendation for cancer genetic counseling was documented in 40% of all genetic counseling summaries and in 59.2% of summaries when NCCN genetic testing criteria for HBOC and/or Lynch syndrome was met. Using chi-squared and logistic regression analysis, these data support that individuals were significantly more likely to receive a recommendation when NCCN genetic testing criteria were met (OR=5.01, p<.001) or when the family history contained two or more types of cancer (OR=2.24, p=.02). Overall, this study identified the NCCN genetic testing criteria for HBOC and Lynch syndrome for which recommendations for cancer genetic counseling were commonly missed. This characterization suggests that continuing education for prenatal and preconception genetic counselors on updated NCCN guidelines may be helpful for improving rates of cancer genetic counseling referrals, uptake of genetic testing, and cancer screening recommendations.

Comparison of hereditary breast and ovarian cancer syndrome and sporadic ovarian cancer in ovarian cancer BRCA mutations

Objective: To study the difference between BRCA gene mutations in hereditary breast and ovarian cancer syndrome (HBOC) and in sporadic ovarian cancer (SOC). Methods: This study was for exploratory research, the inclusion criteria were 284 patients with ovarian cancer admitted at Shanxi Provincial Cancer Hospital from November 2018 to December 2019, with high-throughput DNA sequencing including the full coding regions and exon-intron link regions of BRCA1 and BRCA2 gene. Pathogenic mutations in the BRCA gene of patients with ovarian cancer were collected and mutation site analysis was performed to compare phenotypic differences in pathogenic mutations between HBOC syndrome and SOC patients. Results: (1) Of the 284 ovarian cancer patients, seventy-seven had BRCA pathogenic mutations with a mutation rate of 27.1% (77/284), with BRCA1 mutation rate of 19.7% (56/284), BRCA2 gene 6.7% (19/284) and BRCA1/2 common mutation rate of 0.7% (2/284). Of the 284 patients with ovarian cancer, the pathogenic mutation rate in the BRCA gene in HBOC syndrome patients was 43.8% (32/73), which were significantly higher than that in SOC patients [21.3% (45/211); χ²=13.905, P<0.01]. Among BRCA1 gene mutation, the mutation rate in HBOC syndrome was higher than that of SOC [87.5% (28/32) vs 62.2% (28/45)], the BRCA2 gene mutation rate in patients with HBOC syndrome was lower than that in SOC patients [6.2% (2/32) vs 37.8% (17/45)], and there were statistically significant differences (all P<0.05). Two of the 77 patients with pathogenic mutations in the BRCA gene were multisite mutations, including one simultaneous two site mutation, one simultaneous three site mutation. There were 80 mutation sites with frameshift deletion mutations (55.0%, 44/80) and nonsense mutations (31.2%, 25/80). (2) Of the 73 patients with HBOC syndrome, 32 cases had pathogenic mutations in BRCA gene, including 28 cases in BRCA1, mainly in exon 11 and 24 (9 and 7 cases, respectively), and only two cases in BRCA2, both in exon 11; another two had multiple locus mutations. Of the 211 patients with SOC, 45 cases had pathogenic mutants in BRCA gene, including 28 cases in BRCA1, mainly in exon 11 and 24 (15 and 2 cases, respectively), and 17 cases in BRCA2, mainly in exon 11 (11 cases). (3) Thirty-four pathogenic mutation sites in BRCA gene were found newly, twenty of them were located in the BRCA1 gene, including a locus located on the intron 6, 301+1G>A, and the remaining 19 sites were located on the exons, including 283_286delCTTG, 68_69delAG, 132C>T, 514_547+3del37, 742delA, 1126_1129delAATA, 1196delA, 1352_1364del, 1465G>T, 2171delC, 2341G>T, 3359_3363delTTAAT, 4085_4086ins11, 4161_4162delTC, 4165_4166delAG, 4258G>T, 4338_4339del8insAGAA, 4468G>T, and 4783delA; fourteen sites were located in the BRCA2 gene, including a locus located on the intron 7, 631+1G>A, and the remaining 13 sites were located on the exons, including 2648delT, 2914A>T, 2950_2951insG, 4357+1G>A, 5054C>T, 5257A>T, 5291_5292insTC, 5913delT, 3593delA, 6091_6092insA, 6135_6136delTT, 7452delT, 9097_9098insA. A tal of 28 repeat mutations were located in the BRCA1 gene; among them, the site 5470_5477del8 was repeated 6 times, while 3 times in 981_982delAT. Conclusions: Patients with HBOC syndrome have a significantly higher rate of pathogenic mutation in the BRCA gene than that in patients with SOC. BRCA gene pathogenic mutation sites in HBOC syndrome patients occur commonly in exon 11 and 24 of BRCA 1 gene, while SOC patients occur mainly in exon 11 and 24 of BRCA1 gene and exon 11 of BRCA2 gene. The two loci of BRCA1∶5470_5477del8, BRCA1∶981_982delAT may be ancestor mutations in Chinese ovarian cancer patients, and 34 newly discovered pathogenic mutations in the BRCA gene, enriching the BRCA gene mutation spectrum in the Chinese population.

162P Prevalence and spectrum analysis of germline BRCA1 and BRCA2 variants of unclear significance in HBOC Syndrome: Decoding the mysterious signals of the genome

About 10-20% of hereditary breast and/or ovarian (HBOC) cancer patients undergoing germline BRCA1/2 genetic testing harbour Variants of Uncertain Significance (VUS). Poor is the knowledge about the prevalence of germline BRCA1/2 VUS in HBOC patients of Southern Italy. Our study is aimed at describing the spectrum of these variants detected in HBOC patients in order to improve the patient’s stratification with the identification of potentially high-risk BRCA variants helpful for patient clinical management.

Single stage risk-reducing breast and gynecologic surgery for hereditary predisposition to breast and ovarian cancer

Objectives: We sought to evaluate the perioperative outcomes of patients undergoing single-stage breast and gynecologic surgery for either breast cancer or a hereditary breast and ovarian cancer syndrome (HBOC). Methods: All patients with documented genetic testing undergoing single-stage breast and gynecologic extirpative surgery for breast cancer or an HBOC syndrome with or without immediate breast reconstruction were included. Perioperative outcomes including intraoperative, Results: Forty-three patients underwent single-stage surgery between September 2015 and July 2020 at a single academic tertiary referral hospital. Most patients underwent combined surgery for breast cancer (81.3%) and concurrent gynecologic prophylaxis (97.7%). Median patient age was 48 years and median BMI was 26.8 kg/m2. There were 33 patients (76.7%) with a pathogenic genetic mutation, the most common of which was BRCA1 (41.9%). All breast surgeries were mastectomies, 90.7% of which were bilateral; 48.8% included axillary lymph node dissection. The majority (88.4%) of breast extirpative procedures were followed by immediate reconstruction. The gynecological procedures were most commonly performed via conventional laparoscopy (55.8%): Fifty-eight percent of patients underwent total hysterectomy and bilateral salpingo-oophorectomy (BSO) and 37.5% underwent BSO alone. Median total operative time was 459.5 minutes (74-818 min). Median length of hospital stay was four days (1-14 d), and median estimated blood loss was 25cc (25-200 cc). The only intraoperative complication was a breast reconstructive flap failure that required vascular reanastomosis. Overall, 34.8% of patients had a complication. Complications during the first 30 post-operative days included four readmissions for reoperation, one venous thromboembolism (VTE), two transfusions, and nine complications of breast surgery (three hematomas, three wound dehiscences, and three surgical site infections). Six of these patients required reoperation Download : Download high-res image (91KB) Download : Download full-size image Conclusions: Single-stage breast and risk-reducing gynecologic surgeries are associated with similar complication rates to multi-stage surgeries with the benefit of providing the patient with a single recovery period. Further studies are encouraged to motivate multi-disciplinary collaboration with the ultimate goal of shorter overall recovery time for patients with breast cancer or an HBOC syndrome.

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening.

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.

Abstract PS9-37: Hereditary breast and ovarian cancer syndrome (HBOC) diagnosis impacts more the life quality of women than men: A case-control report

Abstract INTRODUCTION: HBOC syndrome is directly associated with a variant in BRCA1/2 genes and the diagnosis may increase anxiety and depression levels because of the need for preventive measures. Psychic impacts on women with mutations have been further explored in the literature, although the emotional aspects linked to the diagnosis in male breast cancer is poorly known. AIM: This work aimed to compare the anxiety, depression, and quality of life levels in male and female cancer patients HBOC-suspected, immediately after the result of the genetic test. METHODOLOGY: A retrospective case-control study was carried out with five men matched for age with 39 women, both with National Comprehensive Cancer Network (NCCN) criteria for HBOC. The Hospital Anxiety and Depression (HAD) scale and the WHOQOL-bref quality of life inventory were used. Sociodemographic, clinical, molecular, and psychological data were analyzed using χ2/Fisher's exact and Mann-Whitney, Friedman/Dunn, and Wilcoxon tests (SPSS, 20.0; p &amp;lt;0.05). RESULTS: All patients were &amp;gt;45 years old, all recruited women had breast cancer as the primary tumor and eight of them (20.5%) had ovary cancer. We had two male breast cancer and three prostate cancer Gleason&amp;gt;7. Sociodemographic characteristics did not differ between the genders (p&amp;gt; 0.05). Men had a higher prevalence of pathogenic mutation (p=0,031). Women had a higher prevalence of BRCA1 mutations (p=0,014) while men had of BRCA2 mutation (p=0,001). There was no difference in the anxiety and depression levels immediately after receiving the result, but it was observed that only women had lower quality of life in the physical domain (p=0,048). This domain showed the lowest scores in female patients (p&amp;lt;0,001). Although men have a higher prevalence of the pathogenic mutation in BRCA1/2, the emotional impact is greater in women whose impact on the physical domain may be directly associated with cancer treatment, which may have physical and psychological consequences, negatively affecting the quality of life of these women. CONCLUSION: These results reinforce the need to address the psycho-emotional aspects of women with HBOC, to promote better treatment coping, providing a better quality of life. Research Sponsor: Ministerio da Saude, Brasil (PRONON) Citation Format: Francisca Fernanda Barbosa Oliveira, Paulo Goberlanio de Barros Silva, Isabelle JoyceLima Silva-Fernandes, Clarissa Gondim Picanço-Albuquerque, Maria Claudia dos Santos Luciano, Maria Júlia Barbosa Bezerra, Rosane Oliveira Sant´anna, Flavio Silveira Bitencourt, Marcos Venicio Alves Lima. Hereditary breast and ovarian cancer syndrome (HBOC) diagnosis impacts more the life quality of women than men: A case-control report [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-37.

A patient with HBOC syndrome who was referred to a university hospital using the JOHBOC cooperation system, was diagnosed with a pathogenic variant of BRCA1, and treated by RRSO: a case report

A patient with HBOC syndrome who was referred to a university hospital using the JOHBOC cooperation system, was diagnosed with a pathogenic variant of BRCA1, and treated by RRSO: a case report

Stepwise approach to hereditary breast cancer and evaluation of BRCA negative patients

Aim: Hereditary breast cancer is one of the components of hereditary breast-over cancer syndrome (HBOC) that results with multiple cancer predisposition. Heterozygous mutations of BRCA1 and BRCA2 that have crucial roles in DNA repair are responsible for about 12-25% of the patients. 25 different genes have been identified to be a causal factor in the patients whose BRCA tests are negative. Most of these genes are involved in functionally related genome maintenance pathways with BRCA1 and BRCA2. We aimed to investigate genes other than BRCA1/2 to determine breast cancer etiology. Materials and Methods: Of the 230 patients diagnosed with breast cancer, 38 patients with no mutation in BRCA1 / 2 were evaluated. Hereditary breast cancer panel was designed with QIAseq solution. The sequencing process was performed on the Illumina MiSeq system. The data analyses were performed on QIAGEN Clinical Insight analyze software. Results: The genes associated with hereditary breast cancer were studied with the new generation sequencing method in 38 of the patients without pathogenic or VUS variants. Pathogenic/likely pathogenic variants were detected in 3 (7.8%) of 38 patients, while VUS was detected in 10 (26.3%) patients. Of these 22 genes, c.312C A (p.Tyr90Ter) in MUTY, c.1225C T (p.Arg409Trp) in STK11, c.1690C T (p.Gln564Ter) variant in BARD1 interpreted as pathogenic.Conclusion: Our data provide insight into the genetics of HBOC syndrome in Turkey. These studies will help to improve the clinical management and better risk assessment of hereditary breast and ovarian cancer.

Pathogenicity reclassification of two BRCA1/BRCA2 exonic duplications after identification of genomic breakpoints and tandem orientation

The genomic consequence and clinical interpretation of large duplications are difficult to infer without determining the location and orientation of the duplicated sequence. We aimed to characterize two intragenic duplications detected in two hereditary breast and ovarian cancer syndrome (HBOC) families, namely BRCA1 exon 4 to 6 and BRCA2 exon 17 to 18, previously detected by multiplex ligation probe amplification and initially classified as variants of unknown significance. Using long range PCR, with duplication-specific primers, we were able to ascertain the genomic breakpoints and observed that the two rearrangements occurred in tandem and in direct orientation. The BRCA1 c.134+440_441+870dup and BRCA2 c.7806-2083_8332-1512dup duplications here identified are predicted to cause frameshifts that create a premature stop codon and were reclassified as pathogenic. Furthermore, both families present phenotypic traits typical of HBOC syndrome. We also observed that the genomic breakpoints of these two duplications occurred within highly homologous Alu elements. Concluding, we characterized two in tandem BRCA1 and BRCA2 duplications that likely occurred by Alu-mediated homologous recombination, allowing identification of the underlying cause of the HBOC syndrome in these families.

Abstract 3531: A novel germline mutation in the non-coding region of BRCA2, c.-40+1 G&amp;gt;A, is associated with hereditary breast cancer

Abstract Background: BRCA2 plays an important role in DNA double-strand break repair, especially homologous recombination repair, to maintain genomic stability across generations. Germline mutations of BRCA2 increase a lifetime risk of developing breast and ovarian cancer, which is termed hereditary breast-ovarian cancer syndrome (HBOC). In this study, we identified a novel pathogenic mutation at a splicing site in the non-coding region of BRCA2, which is not covered by commercially-available BRCA2 genetic tests, in a breast cancer patient with a familial history of HBOC-related cancers. This germline mutation was previously reported in a Fanconi anemia family as well (Bakker J.L. et al., 2014). Methods: Genomic DNA and total RNA were isolated from peripheral blood mononuclear cells (PBMCs) of the breast cancer patient. The oncogenic mutation screening with genomic DNA was conducted using the next generation sequence (NGS)-based panel analysis of 147 familial cancer (FC)-associated genes, termed the National Cancer Center (NCC) Oncopanel FC test. Immunohistochemistry of BRCA2 was conducted using the surgical breast tumors as well as adjacent normal breast tissues of the patient. The sporadic breast tumors without BRCA2 mutation was used as a control. Results: The NCC Oncopanel FC test detected the novel germline mutation at c.-40+1 G&amp;gt;A in the non-coding region of BRCA2 in a breast cancer patient, who has a familial history of HBOC-related cancers. The germline mutation was a mono-allelic mutation found in the maternal allele and not in the paternal allele. Since the patient has a single nucleotide polymorphism (SNP) at c.-26 G&amp;gt;A in the paternal allele, this SNP site was used to identify the paternal-derived BRCA2 mRNA. RT-PCR analysis in the patient's PBMCs only detected the paternal-derived transcripts harboring c.-26 G&amp;gt;A, suggesting that the transcripts of the maternal-derived BRCA2 allele with c.-40+1 G&amp;gt;A mutation would not be expressed, or not be stabilized, in the patient's PBMCs. Immunohistochemical analysis revealed that BRCA2 protein was detected in normal mammary epithelial cells of the breast tissues. In the malignant tissues, however, BRCA2 protein was potently downregulated in the BRCA2-mutant breast cancer cells but not in the BRCA2 wild-type breast cancer cells, assuming that the mutant cancer cells may have the second hit in the paternal allele of BRCA2. These findings suggest that this novel BRCA2 germline mutation could be involved in loss of function of BRCA2 leading to HBOC syndrome. Conclusions: We identified the novel germline mutation in the non-coding region of BRCA2, c.-40+1 G&amp;gt;A, which appears to be involved in hereditary breast cancer. Citation Format: Yumi Hakozaki, Yumi Fujimoto, Susumu S. Kobayashi, Mineko Ushiama, Yumie Hiraoka, Kenichi Harano, Takahiro Kogawa, Satoshi Fujii, Takeshi Kuwata, Teruhiko Yoshida, Akihiro Ohashi, Toru Mukohara. A novel germline mutation in the non-coding region of BRCA2, c.-40+1 G&amp;gt;A, is associated with hereditary breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3531.

Genetic counselors' perspectives on population-based screening for BRCA-related hereditary breast and ovarian cancer and Lynch syndrome.

Early identification of those with BRCA-related Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch syndrome has the potential for early cancer detection and/or prevention; as such, these conditions are considered Tier 1 genetic conditions by the U.S. Center for Disease Control and Prevention. Given the decreasing cost of genetic testing, population-based screening (PBS) for such conditions may be the next step toward cancer prevention. This study aimed to understand genetic counselors' perspectives toward offering PBS for the Tier 1 conditions BRCA-related HBOC and Lynch syndrome. An online survey was distributed to 3,609 members of the National Society of Genetic Counselors. A total of 367 individuals participated in the study. Fifty percent of respondents felt that PBS for inherited cancer should not be offered; 93.3% felt that the current healthcare system is unprepared for implementation of PBS. However, most respondents agreed that PBS should be implemented within the next 10years. Attitudes toward offering PBS were associated with respondents' work setting, cancer specialization, and perceived preparedness (p's<0.05). The most commonly reported barriers to the implementation of PBS were shortage of genetic professionals and lack of infrastructure. Data in this study provide evidence that infrastructural barriers and educational gaps of non-genetic professionals would need to be addressed before successful integration of PBS into the healthcare system.

Abstract P2-09-11: Prevalence of patients with indication of genetic evaluation for hereditary breast and ovarian syndrome in the Brazilian cohort study - AMAZONA III

Abstract INTRODUCTION: The evaluation of an individual with risk of hereditary breast cancer is based on the patient's family history and the characteristics of the neoplasia. BRCA1 and BRCA 2 are the most common genes associated with hereditary predisposition for breast or ovarian cancer. The evaluation of an individual with risk of hereditary breast cancer is key to identify patients with indication to BRCA test. Recent studies in US suggests that 31 to 34% of patients with breast cancer should be referred for genetic evaluation. In Brazil, the proportion of BC patients with indication to genetic evaluation is unknown. OBJECTIVE: To describe the prevalence of breast cancer patients enrolled in the AMAZONA III study with indication for genetic evaluation considering the criteria for hereditary breast and ovarian cancer syndrome (HBOC). METHOD: We evaluated the database of the AMAZONA III observational, prospective cohort study which included 2950 patients newly diagnosed with BC in the period of 2016-18 within 23 Brazilian sites. The criteria used to select patients who should be referred for genetic testing were extracted from the National Comprehensive Cancer Network (NCCN) guideline 2018. The characteristics of interest were summarized through descriptive statistics. RESULTS: A total of 1094 (37%) BC patients had at least one criteria for HBOC syndrome test. The most common criteria for testing was age equal or inferior 45 years (27%), BC diagnosis under 50 years and family history of breast cancer (13.5%). From the 2950 enrolled patients, 651 (22%) had the information about whether an evaluation of BRCA test was performed. Of them only 45 (6.9%) performed BRCA test, one patient from public health system and the others from private health system and from those tested 18 (40%) had an identified pathogenic mutation. CONCLUSION: A high proportion of patients diagnosed with BC in Brazil have a criteria for HBOC syndrome testing. Nonetheless a few patients have access to genetic counseling and BRCA test, especially in the public health system. Therefore its critical to implement health policies to facilitate the access to specialized care in hereditary cancer. Frequency of each criteria regarding all 2950 patientsTotal - n (%)Missing - n (%)&amp;lt;=45 years806 (27.32)62 (2.10)&amp;lt;= 60 years and molecular subtype triple negative234 (7.93)681 (23.08)Family history of ovarian cancer101 (3.42)214 (7.25)&amp;lt;= 50 years and family history of breast cancer388 (13.15)214 (7.25)&amp;lt;= 50 years and personal history of breast cancer26 (0.88)142 (4.81)Personal history of ovarian cancer4 (0.14)142 (4.81) Citation Format: Alessandra BorbaAnton de Souza, Daniela Rosa, Antonio LuiZ Frasson, Felipe Pereira Zerwes, Nathalia Cunha Rossato, Patricia Asthon-Prolla, Sergio Simon, Jose Bines, Carlos Barrios, Alessandra Morelle, Carlos AlbertoSampaio Filho, Max Mano, Rafaela Gomes, Gustavo Werutsky. Prevalence of patients with indication of genetic evaluation for hereditary breast and ovarian syndrome in the Brazilian cohort study - AMAZONA III [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-11.

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

BackgroundThe Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20–30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients.MethodsWe systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms.ResultsWe identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.ConclusionsThis study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.

Analysis of variators in the brca1 and brca2 genes by ngs in patients from central brazil with suspected hboc syndrome: a new pathogenic variant identified

About 10‒15% of breast cancer cases are due to deleterious germ changes, more than half of which are located in the BRCA1 or BRCA2 genes. The screening of variants in these genes for patients at risk brings benefits for better clinical management of the patient as well as for the prevention of disease recurrences both in the proband and in their relatives. The profile of genetic variants is little known to the Brazilian population and, to date, there are no published data for the population of the central region of the country. This study aimed to analyze the profile of pathogenic variants (VP) and of uncertain significance (VUS) in the BRCA1 and BRCA2 genes in this population. We selected 102 patients seen at Hospital das Clínicas, Universidade Federal de Goiás, with clinical diagnosis of invasive ductal carcinoma that met the criteria of the National Comprehensive Cancer Networking 2016/2 for hereditary breast and ovarian cancer syndrome. A collection of 4mL of peripheral blood was carried out and submitted to subsequent extraction of genomic DNA, carried out using the PureLink kit (Invitrogen). The genes in question had all their exon-intron regions sequenced using the MiSeq device (Illumina) and the raw data were evaluated using the Sophia DDM software. The risk of in silico pathogenicity of the VUS was analyzed by the software POLYPHEN2, MutationTaster, SIFT, ESP5400, G1000, GnomAD. Of the total of 102 patients evaluated in this study, 22 (21.56%) had PV or VUS in the BRCA1 or BRCA2 genes. Of these, 16 patients (72.81%) had pathogenic variants, eight with PV in BRCA1 (c.5266dupC (2), c.3331_3334delCAAC, c.211A&gt;G, c.3228_3229delAG, c.3700_3704delGTAAA, c.4484G&gt;T and c.5305_5306ins20) and eight with PV in BRCA2 (c.156_157insAlu, c.4829_4830delTG, c.8488-1G&gt;A, c.6405_6409delCTTAA (3), c.517-1G&gt;A, c.2808_2811delACAA). A total of 7 patients (31.8%) presented VUS in these genes, one in the BRCA1 gene (c.179A&gt;G) and five in the BRCA2 gene (c.280C&gt;T, c.811G&gt;A, 1096T&gt;G, 1441A&gt;G and c.5270A&gt;G) of which only the variant c.1441A&gt;G had low pathogenic potential in silico. A new PV still not described in the literature was also identified, variant c.5305_5306ins20 in the BRCA1 gene. These data suggest that all patients at risk in this population should be evaluated for PV or VUS in the BRCA1 and BRCA2 genes since the presence of these variants can help in the patient's prognosis and disease prevention.

Increased Yield of Hereditary Cancer Risk Assessment in a GI Office Practice Utilizing NCCN Guidelines and Panel Testing

Introduction: Deleterious mutations associated with an increased risk of cancer are prevalent in the general population and remain undetected in the vast majority of patients until cancer develops. Hereditary cancer assessment is an important part of patient evaluation, especially upon initial presentation to a clinician. Customarily, specialists focus on family history specific to their specialty. Gynecologists and breast surgeons query patients about family history of breast and ovarian cancer (ie HBOC syndrome) while gastroenterologists & colorectal surgeons focus on Lynch syndrome. Recently, we broadened our cancer risk assessment in our GI population by utilizing the more broad NCCN guidelines rather than focusing on GI criteria. Methods: We employed a digital survey on a tablet using NCCN guidelines. The patients were presented with the tablet prior to being seen by the physician. If the survey indicated that the patient was at increased risk for hereditary cancer, further evaluation and possible testing was offered. Results: 2,239 patients were screened: 639 patients (29%) = high risk, 76% met HBOC criteria, 12% met Lynch criteria, and 12% both; 381 interested in genetic evaluation (60%), 374 were tested (98%): 27 were positive for deleterious mutations: 9 APC low penetrance (7 of 9 Ashkenazi Jewish - elevated colon cancer risk), 6 Monoallelic MUTYH, 3 ATM, 2 APC, 2 BRCA1, 2 BRCA2, 1 CHEK2, 1 PMS2, 1 RAD51D. 26/27 mutations (96%) with GI-related cancer risk - 3 single-site testing=24 mutations via panel testing & 23 (95.8%) with GI-related cancer risk. 14/23 (61%) had HBOC-related indications vs. 9 (39%) with Lynch indications. Overall, 18 mutations (67%) are GI-related genes (monoallelic MUTYH, APC low penetrance, APC & PMS2) - 2 were single-site testing, ie 16 mutations were identified by panel testing. 8/16 (50%) = HBOC-related indications & 8 (50%) were Lynch indications Conclusion: In an attempt to identify individuals with an increased risk of hereditary cancer in our practice, we expanded our assessment based on overall risk by utilizing NCCN guidelines rather than focused GI criteria. We detected 27 previously unidentified mutations in our population of 2239 screened patients. Expanding the survey questions to include HBOC risks and using panel testing, resulted in a 2.5 fold increase in the detection of GI related mutations. This experience suggests that hereditary risk assessment should address overall cancer risk and not be limited to focused assessment.

Validation of NCCN criteria for genetic testing in HBOC syndrome in Brazil

Validation of NCCN criteria for genetic testing in HBOC syndrome in Brazil

Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer

Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype. BRCA1 promoter hypermethylation and the BRCAness phenotype of BC cell lines were also studied. The purpose of this study was to determine the metabolic signature of HBOC syndrome and TNBC patients and to evaluate the potential contribution of the metabolites identified to the genetic diagnosis of breast cancer. The present results show the existence of a differential metabolic signature for BC cells based on the BRCA1 functionality. None of the studied BC cell lines presented hypermethylation of the BRCA1 promoter region. We provide evidence of the existence of free methylated nucleotides capable of distinguishing plasma samples from HBOC patients as BRCA1-mutated and BRCA1 non-mutated, suggesting that they might be considered as BRCA1-like biomarkers for TNBC and HBOC syndrome.