Hereditary Cancer Predisposition Research Articles

Rolul medicului de familie în diagnosticul precoce al cancerului colorectal

The incidence of colorectal cancer is increasing. It is currently the third most common cancer, after lung and breast cancer. Despite the increased incidence, recent advances in early detection, performing the screening according to the recommendations and treatment options have reduced colorectal cancer mortality. The role of the family doctor is to advise and to identify non-modifiable risk factors (age, male sex, race, family history, inflammatory bowel disease) as well as modifiable ones (tobacco consumption, low-fiber, high-fat and high carbohydrate diet, a sedentary lifestyle, obesity), in order to avoid these risk factors by developing a personalized plan for the prevention and early detection of colorectal cancer depending on the individual risk. Genetic testing and a more comprehensive family history documentation by the family doctor can enable those with a hereditary predisposition for the colorectal cancer to take preventive measures. Applying evidence-based prevention strategies reduces the prognosis of colorectal cancer and reduces mortality. Colorectal cancer has an increased survival rate if diagnosed early and treated properly.

Clinical consequences of BRCA2 hypomorphism

The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37–54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.

1850P Communication patterns and cascade testing among pathogenic variant carriers

Cascade testing (CT) for hereditary cancer predisposition syndromes in families of pathogenic variant (PV) carrier enables precisely targeted surveillance and risk-reducing strategies. Genetic test results communication within families is key to enhance CT. The frequency and factors associated with carriers’ disclosure of test results to family members and CT were studied at 2 cancer centers in Mexico.

Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review.

Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.

Hereditary colorectal cancer syndromes and the COVID-19 pandemic: results from a survey conducted in patients enrolled in a dedicated registry.

PurposeThe coronavirus 2019 (COVID-19) pandemic has had profound consequences also for non-infected patients. This study aimed to evaluate the impact of the pandemic on the quality of life of a population with hereditary gastrointestinal cancer predisposition syndromes and on the surveillance/oncological care program of patients enrolled in a dedicated registry.MethodsThe study was conducted by means of an online self-report survey during the first Italian national lockdown. The survey comprised four sections: demographics; perception/knowledge of COVID-19; impact of the COVID-19 pandemic on surveillance and cancer care; health status (SF-12 questionnaire).Results211 complete questionnaires were considered. 25.12% of respondents reported being not at all frightened by COVID-19, 63.98% felt “not at all” or “a little” more fragile than the healthy general population, and 66.82% felt the coronavirus to be no more dangerous to them than the healthy general population. 88.15% of respondents felt protected knowing they were monitored by a team of dedicated professionals.ConclusionPatients with hereditary gastrointestinal cancer predisposition syndromes reported experiencing less fear related to COVID-19 than the healthy general population. The study results suggest that being enrolled in a dedicated registry can reassure patients, especially during health crises.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11136-021-02973-4.

Classification of MSH6 Variants of Uncertain Significance Using Functional Assays.

Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.

Following NCCN guidelines within one hospital system in the United States: Comparison between cancer centers and genetic counselor utilization.

Genetic testing is an instrumental tool used to determine whether an individual has a predisposition to certain cancers. Knowing of a hereditary cancer predisposition may allow a patient and their family to consider high-risk screening or risk-reducing options. Genetic counselors work with physicians to identify patients at increased risk for genetic testing using available guidelines such as those provided by the National Comprehensive Cancer Network (NCCN). Information within one hospital system's cancer registry was used to identify individuals who qualify for genetic testing. This includes patients with a history of cancer of the breast (diagnosis ≤45, triple negative (TN) ≤60, and male), ovaries, colon (diagnosis ≤50), or uterus (diagnosis ≤50). Within this hospital system's registry, there are six cancer centers. Data were collected from cancer centers that utilized genetic counselors (GCs), and cancer centers that did not (non-GC) to determine whether there was a difference in genetic testing rates between GC and non-GC cancer centers. An analysis of 695 patients demonstrated a significantly higher proportion of eligible patients undergoing genetic testing at the GC cancer centers than at the non-GC cancer centers (91.6% versus 68.7%, p<.001). Further analysis of specific cancers showed a significantly higher uptake of genetic testing for eligible patients with colon cancer (90.8% versus 50%, p<.001), breast cancer ≤45 (99.5% versus 86%, p<.001), and ovarian cancer (91.3% versus 62.8%, p<.001) at the GC cancer centers than at the non-GC cancer centers. There was no significant difference in the proportion of testing of TN breast cancer ≤60 or uterine cancer ≤50 between cancer centers. These data suggest that having a GC working within a cancer center increases the ability to identify and offer testing to patients who meet NCCN genetic testing criteria based on their cancer type.

Evaluation of a hybridization capture-based hereditary cancer panel for the ion semiconductor-based next-generation sequencing system

BackgroundThere is an unmet need to use the ThermoFisher Ion sequencing platform with a hybridization capture-based next-generation sequencing(NGS) panel. However, the analytical performance of combining an ion semiconductor-based sequencing system and a hybridization capture-based NGS panel has not been thoroughly evaluated. Therefore, we compared the analytic performance of Illumina's NextSeq and Ion S5 XL using a hybridization capture-based target enrichment method. MethodsWe included 31 clinical samples and NA12878 reference material for comparing two different NGS instruments using a hybridization capture-based panel. The hybridization-based capture hereditary cancer predisposition (HCP) panel was designed for Ion S5 XL Sequencer and Illumina platforms, respectively. ResultsWe obtained comparable data involving sequencing run metrics and analytical performance of two different NGS systems using a hybridization-based capture panel designed for each NGS platform. The sensitivity, specificity, and accuracy of single-nucleotide variant and indel calling were 97.06%, 100%, and 100% for the Ion S5™ XL system and 98.53%, 100%, and 100% for NextSeq 550Dx platform, respectively. ConclusionsThis study demonstrated that a hybrid capture panel kit can be successfully implemented using the ThermoFisher Scientific Ion S5 XL instrument and offers the opportunity to select a variety of hybridization-based capture panels from various manufacturers.

Precision Therapy for Brain Tumors in Hereditary Syndromes.

Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.

Investigation of Hereditary Cancer Predisposition Genes of Patients with Colorectal Cancer: Single-centre Experience.

To investigate the genetic causes of colorectal cancers (CRCs); and to determine the genotype-phenotype correlation. Descriptive study. Department of Medical Genetics, Diskapi Yildirim Beyazit Training and Research, Hospital, Ankara, Turkey, between January 2018 and January 2020. 59 cancer susceptibility genes of 41 patients, included in the study and diagnosed with CRC, were examined using next generation sequencing (NGS) technique. Statistical analysis of the possible relationships among the mutation carrier status of the patients and the parameters of gender, age at diagnosis, and family cancer history, were performed. The mean age at diagnosis of all CRC patients was 48.7 years (range 28-74). Mutations in MLH1, MSH6, CHEK2, PMS2 and MUTYH genes were detected in 10 patients (24.4%). The mean age at diagnosis of CRC was 46.2 years in those who carried the mutation, while it was 49.5 years in those without. Carriers and non-mutation carriers, when compared in terms of age at diagnosis, gender, family cancer history, no significant difference was observed. Genes that may cause susceptibility to cancer may play a role in the etiopathogenesis of the CRC. NGS-based multigene panels allow these genes to be detected in the patient and to identify an inherited cancer syndrome. Key Words: Colorectal cancer, Lynch syndrome, Hereditary cancer, Gene, Next generation sequencing.

A Retrospective 5-Year Single Center Study Highlighting the Risk of Cancer Predisposition in Adolescents and Young Adults.

Simple SummaryGenetic disposition to malignancies represents a significant factor in the diagnosis and treatment of cancer patients, as well as for pre- and post-treatment care of patients and their relatives. In our work, we point out the specific distribution of malignancies in adolescents and young adult patients (AYAs), highlighting the association with an increased risk of genetic predisposition. Genetic disposition requires special attention, especially for AYA patients. Knowledge of an underlying inherited cancer susceptibility facilitates individualized therapies and targeted efforts in cancer surveillance and prevention. With our work, we seek to contribute to a more consistent integration of the screening of AYAs for hereditary cancer predisposition into daily practice in the future.The knowledge of inherited cancer susceptibility opens a new field of cancer medicine. We conducted a retrospective single-center cohort study. Data of AYA cancer patients registered between January 2014 and December 2018 were analyzed. The median age at cancer diagnosis of 704 patients (343 males, 361 females) was 32 years (range, 15–39 years), median follow-up was 181 days (range, 1–1975 days). Solid tumors were diagnosed in 575 (81.7%) patients, hematologic malignancies in 129 (18.3%) patients. Multiple primary cancers were reported in 36 (5.1%) patients. Malignancies that may be indicators of inherited cancer susceptibility were diagnosed in 2.6% of patients with cancers of the endocrine system, in 73% of cancers of the gastrointestinal system, in 88% of tumors of the central nervous system, in 92% of cancers of the urinary tract, and in 59% of head and neck tumors. In addition, all patients with breast cancer, sarcoma, and peripheral nerve sheath tumor were in need of genetic counselling. In sum, at least 181 of 704 (25.7%) AYA cancer patients presented with malignancies suspicious of harboring pathogenic germline variants. Evaluation of AYA cancer patients for hereditary cancer predisposition needs to be integrated into daily practice.

The Functional Hallmarks of Cancer Predisposition Genes.

The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, BRCA1, BRCA2, MMR genes) and/or cell cycle (eg, APC, RB1). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation. We propose here that, given the variety of pathways that may ultimately affect genome integrity and cell proliferation, the model of cancer genetic predisposition needs to be expanded to account for diverse mechanisms. This synthesis calls for modeling and multi-omic studies applying novel experimental and computational approaches to understand cancer genetic predisposition.

Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.

Li‐Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large‐scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA‐binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison with those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon.

Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.

A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer.

Germline mutations in DNA repair-related genes have been recently reported in cases with familial non-medullary thyroid carcinoma (FNMTC). A Portuguese family from the Roma ethnic group with four members affected with papillary thyroid carcinoma (PTC), and three members with multinodular goiter (MNG) was identified. The aim of this study was to investigate the involvement of DNA repair-related genes in the etiology of FNMTC in this family and in the Roma ethnic group. Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing. Sanger sequencing was used for variant confirmation and screening. Twelve polymorphic markers were genotyped for haplotype analysis in the CHEK2 locus. A germline pathogenic frameshift variant in the CHEK2 gene [c.596dupA, p.(Tyr199Ter)] was detected in homozygosity in the proband (PTC) and in his brother (MNG), being heterozygous in his mother (PTC), two sisters (PTC), and one nephew (MNG). This variant was absent in 100 general population controls. The screening of the CHEK2 variant was extended to other Roma individuals, being detected in 2/33 Roma patients with thyroid cancer, and in 1/15 Roma controls. Haplotype segregation analysis identified a common ancestral core haplotype (Hcac), covering 10 Mb in the CHEK2 locus, shared by affected CHEK2 variant carriers. Analysis of 62 individuals CHEK2 wild-type indicated that none presented the Hcac haplotype. The estimated age for this variant suggested that it was transmitted by a relatively recent common ancestor. We identified a founder CHEK2 pathogenic variant, which is likely to underlie thyroid cancer and other cancer manifestations in the Roma population.

Factors Affecting Genetic Consultation in Adolescent and Young Adult Patients With Sarcoma.

Given a link between sarcomas and hereditary cancer predisposition syndromes, including Li-Fraumeni syndrome, the consideration for genetic counseling is recommended for all adolescent and young adult (AYA) patients diagnosed with sarcoma. The aim of this study was to evaluate factors influencing genetic consultations in AYA patients with sarcoma at the University of Wisconsin (UW). A retrospective chart review was performed on AYA patients diagnosed with sarcoma between the ages of 15 and 39 years who were seen at least once between 2015 to 2019 at UW. Our chart review identified discussions regarding genetics, referrals to genetics, genetic consultations, and results of genetic testing. Variables hypothesized to affect patient referrals for genetic consultation were identified a priori. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. We identified 87 AYA patients with sarcoma. Only 19 (22%) of these patients had documentation of a discussion about genetics, 15 (17%) of whom were subsequently referred for genetic consultation. Of these 15 patients, 9 (60%) were seen in consultation. All 9 patients seen by genetics underwent genetic testing, with 4 (44%) of these patients having identified heritable cancer predisposition syndromes. Likelihood for genetics referral was linked most strongly to documented genetics discussion with an oncology provider (P<.001). Despite the recommendation for consideration for genetic counseling in AYA patients with sarcoma, <25% of such patients in our study had a documented discussion about genetics. Supporting this need, all referred patients met criteria for genetic testing, and 44% of tested patients were found to have a heritable cancer predisposition syndrome. These data support the initial conversation by a provider as critical to genetic referral and suggest the need for more specific national recommendations for the genetic evaluation of all AYA patients with sarcoma.

The role of the genetic testing industry in patient education of hereditary cancer: An observational study assessing the quality of patient education videos

ObjectivesGenetic testing (GT) companies have developed patient education videos to supplement or replace pre-test genetic counseling (GC) by certified genetic counselors (CGC). The aim of this study was to assess the quality of these videos compared to the standard of care (SOC). MethodsVideos from four major GT companies were selected from an internet search identifying pre-test patient education videos. A scoring rubric with 22 questions and 36 total points was devised to assess quality metrics, as described by the National Cancer Institute and National Society of Genetic Counselors. Twenty-two individuals with varying genetics expertise (3 gynecologic oncologists, 3 academic generalists, 4 CGC, a genetics community health worker, 3 cancer care navigators, and 8 medical students) scored each video. Scorers were blinded to others' assessments. ResultsInvitae had the highest median score (26/36), followed by Myriad (22/36), Ambry (17.5/36), and Color (15/36). All videos scored highly in explaining DNA basics, cancer development, and hereditary cancer predisposition. All addressed benefits of GT but failed to address potential disadvantages. All scored poorly in explaining medical terms and different GT options. There was variability in addressing patient concerns including cost, privacy, and procedure. ConclusionsThere is significant variation in the content of pre-test patient education videos between GT companies. None of the videos met the SOC for pre-test GC, and none addressed disadvantages of GT, possibly due to a conflict of interest. With improvement in content, accessibility, and use of interactive platforms, these videos may serve as an adjunct to in-person pre-test GC.

Abstract PS16-30: Pms1 gene: A new risk-mutation description?

Abstract INTRODUCTION: PMS1 is part of the cluster of genes related to Mismatch repair genes (MMR) and has been used for investigation in oncogenetic panels. The MMR genes play an important role in tumor control and progression, however, the role of PMS1 in this process still poorly understood and information about its role in increasing the risk of developing a hereditary cancer predisposition syndrome (SHPC) is not completely understood.AIM: To characterize clinically and genetically cancer patients with NCCN criteria for SHPC and carriers of variants in the PMS1 gene.METHODOLOGY: A total of 368 patients suspected of having SHPC, according to the National Comprehensive Cancer Network (NCCN) criteria, were investigated using a Next-Generation Sequencing (NGS) in a panel containing 31 genes. Those that showed variation in the PMS1 gene were grouped, and the tumors were characterized in clinical and molecular aspects.RESULTS: From the 368 patients analyzed, 6.8% (25/368) patients presented Variants of Uncertain Significance (VUS) in PMS1. There was a case of Breast Cancer (BC) with a variant in PMS1, not described in ClinVar, presented in heterozygosis, probably pathogenic [Chr2:190.738,325 NM_000534: c.2578delA: p.(Arg860.Glufs*14)]. Besides, this case was associated with a family history (FH) of cancer breast cancer and melanoma. It is worth mentioning that only one patient was a man, with colorectal cancer (CRC), and his FH also was CRC in addition to stomach cancer. The only change founded was the presence of VUS NM_000534:c.1615A&amp;gt;G:p.(Met539Val) which was identified in 32% (8/25). This VUS was the only genetic alteration observed in 20% (5/25) patients with tumors in the breast (3), thyroid (1), CRC (1), and ovary (1). One of these patients had bilateral breast cancer and thyroid tumor. The patients had their age at diagnosis ranged from 25 to 65 years, with an average of 41 years. The carriers of variants exclusively in PMS1 [40% (10/25)] had different tumors: breast (6); CRC (3); ovary (2); lymphoma (1); thyroid (1); others 32% (n = 8/25) that presented additional VUS in different genes: [ATM (2); BARD (1); CDH1 (1); CHECK2 (1); NBN (1); APC (1); POLE (1)]. Different pathogenic variants (PV) [28% (n = 7/25)] also were identified, besides the previous PMS1 VUS described. The PV was founded in ATM (1); BRCA1 (3); NF1 (1); TP53 (1); MUTYH-heterozygosis (1), and PMS1 (1) gene. A double pathogenic variation was identified in a patient (MUTYH in heterozygosis and BRCA1). The findings in PMS1, even currently classified as VUS, should highlight observation for the clinical and familiar history. Genetic panels should be increasingly used in the investigation of SPHC.CONCLUSION: The roles of PMS1 in cancer progression need further investigations. A few numbers of reports have been identified on germline PMS1 mutations, considering defined disease phenotypes. Therefore, the performance of genetic panels, including the PMS1 gene, in SHPC further investigations will expand our knowledge and permit precise genetic counseling. Citation Format: Isabelle JoyceLima Silva-Fernandes, Clarissa Gondim Picanço-Albuquerque, Maria Claudia dos Santos Luciano, Deysi Viviana Tenazoa Wong, Maria Júlia Barbosa Bezerra, Flavio Silveira Bitencourt, Francisca Fernanda Barbosa Oliveira, Paulo Goberlanio de Barros Silva, Rosane Oliveira Sant´anna, Marcos Venicio Alves Lima. Pms1 gene: A new risk-mutation description? [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 PS16-30.

Abstract PD10-03: Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes

Abstract BACKGROUND: TNBC is among the most aggressive subtypes of invasive breast cancer (BC), and accounts for approximately 10-15% of incidental BC diagnoses. TNBC is associated with early age of onset (median age of diagnosis &amp;lt;50) and disproportionately affects African American women. Breast MRI is currently recommended to screen for BC in women with at least a moderate-to-high lifetime risk of BC (a 2-fold or higher increased risk), and may also be superior to mammogram to screen for TNBC. TNBC has been most closely associated with germline PVs in BRCA1. However, recent studies have suggested that PVs in other genes previously associated with invasive BC may specifically confer high risks of the TNBC subtype. METHODS: Results were analyzed from 627,219 women undergoing clinical multi-gene panel testing at a single US-based commercial laboratory between 5/2013 and 2/2020, including genes associated with hereditary BC and other cancers. Demographic and personal/family history data were collected on a test requisition form. Individuals who had single- or founder-site testing, or prior BRCA1 or BRCA2 testing, were excluded. Multivariable regression analysis was used to examine the association between PVs/suspected PVs and personal history (PHx) of TNBC. Models were adjusted for age, personal/family cancer history, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. RESULTS: In total, 22.4% (140,467/627,219) of women tested reported PHx of BC, of whom 12.8% (17,951/140,467) reported PHx of TNBC. Elevated risks of TNBC were identified in carriers of PVs in 10 genes (see Table). While the highest TNBC risk was associated with PVs in BRCA1 (OR 21.24, 95% CI 19.71-22.88), high risks were also seen for BARD1 (OR 7.05, 95% CI 5.71-8.71), TP53 (OR 5.64, 95% CI 3.08-10.33), PTEN (OR 5.52, 95% CI 2.35-13.00) and PALB2 (OR 5.27, 95% CI 4.55-6.10). Moderate-to-high risks (2-5-fold increased risk) of TNBC were also seen for carriers of PVs in RAD51C, RAD51D, BRCA2, and CDKN2A/P16. By contrast, PVs in NBN, ATM, and CHEK2 were all associated with an apparent decreased risk of TNBC. CONCLUSIONS: PVs in several hereditary cancer genes routinely tested on multi-gene panel tests are associated with high risks (OR&amp;gt;5.0) and moderate-to-high risks (OR 2.0-5.0) of TNBC. These findings can inform practice guidelines about which genes to test when evaluating breast cancer risk and which PV carriers may benefit from intensive breast screening with magnetic resonance imaging (MRI). Odds ratios for TNBC in germline carriers of PV in hereditary cancer risk genesRisk GenePV Positive with TNBCOR95% CIp-valueHigh RiskBRCA1119321.2419.71-22.88&amp;lt;0.001BARD11257.055.71-8.71&amp;lt;0.001TP53125.643.08-10.33&amp;lt;0.001PTEN65.522.35-13.00&amp;lt;0.001PALB22315.274.55-6.10&amp;lt;0.001Moderate-to-High RiskRAD51C864.923.86-6.26&amp;lt;0.001RAD51D454.643.34-6.45&amp;lt;0.001BRCA24884.434.02-4.89&amp;lt;0.001CDKN2A (p16)172.521.52-4.18&amp;lt;0.001Moderate-to-Low RiskBRIP1771.921.51-2.44&amp;lt;0.001Protective EffectNBN140.550.32-0.940.030ATM400.510.37-0.70&amp;lt;0.001CHEK2490.440.33-0.58&amp;lt;0.001HOXB1350.330.14-0.810.015 Citation Format: Michael J Hall, Eric Rosenthal, Susana San Roman, Ryan Bernhisel, John Kidd, Elisha Hughes, Thomas Slavin, Allison Kurian. Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes [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 PD10-03.