Explore the vast range of titles available.

BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44–0.90 for BRCA1; HR = 0.72; 95%CI, 0.47–1.1 for BRCA2 ; p  = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40–1.1 for BRCA1 ; HR = 0.78; 95%CI, 0.44–1.38 for BRCA2 ; p  = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28–0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11–1.25, for BRCA2; p  = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21–0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11–1.9 for BRCA2; p  = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.

We report a series of 21 compound blue nevi, a rare variant in the vast clinical and morphological spectrum of blue melanocytic proliferations. Clinically, they presented in young adults, with a slight female predominance. One-third were located on the dorsum of the foot. Morphologically, all cases displayed large dendritic melanocytes restricted to the deep layers of the epidermis. The compound component was central and evenly distributed. Melanocytic density ranged from scarce isolated cells to a confluent lentiginous architecture. In 12 of the 21 cases, junctional nests of small, bland, weakly pigmented melanocytes were associated. These nests became confluent in the most cellular cases. In all cases, a dermal component was immediately present underneath, mainly of cellular blue nevus-type. All cases were genetically confirmed to harbor either a GNAQ or GNA11 hotspot mutation. This study expands the morphological spectrum of blue nevi that should not be restricted to a strictly intradermal melanocytic proliferation.

Rare sequence variants in the non-coding part of the BRCA genes are often reported as variants of uncertain significance (VUS), which leave patients and doctors in a challenging position. The aim of this study was to determine the pathogenicity of the BRCA1 c.5407-25T>A variant found in 20 families from Norway, France and United States with suspected hereditary breast and ovarian cancer. This was done by combining clinical and family information with allele frequency data, and assessment of the variant’s effect on mRNA splicing. Mean age at breast (n = 12) and ovarian (n = 11) cancer diagnosis in female carriers was 49.9 and 60.4 years, respectively. The mean Manchester score in the 20 families was 16.4. The allele frequency of BRCA1 c.5407-25T>A was 1/64,566 in non-Finnish Europeans (gnomAD database v2.1.1). We found the variant in 1/400 anonymous Norwegian blood donors and 0/784 in-house exomes. Sequencing of patient-derived cDNA from blood, normal breast and ovarian tissue showed that BRCA1 c.5407-25T>A leads to skipping of exon 23, resulting in frameshift and protein truncation: p.(Gly1803GlnfsTer11). Western blot analysis of transiently expressed BRCA1 proteins in HeLa cells showed a reduced amount of the truncated protein compared with wild type. Noteworthily, we found that a small amount of full-length transcript was also generated from the c.5407-25T>A allele, potentially explaining the intermediate cancer burden in families carrying this variant. In summary, our results show that BRCA1 c.5407-25T>A leads to partial skipping of exon 23, and could represent a likely pathogenic variant with reduced penetrance.

Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. Methods From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). Results We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Conclusions Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.

Introduction/BackgroundIn AOC, a better understanding of specific genomic/proteomic alterations beyond tumor BRCA mutation (tBRCAm) and homologous recombination repair deficiency (HRD) is of critical importance for the next generation drug development and patient outcome improvement. The main objective of GREAT was to develop a large AOC clinico-biological database thanks to a tight collaborative network between clinicians, pathologists, biologists and researchers to correlate the real-life clinical and evolutionary characteristics of AOC patients (pts) with new exploratory genomic and molecular tumor abnormalities.MethodologyPts with advanced (FIGO stage 3 or 4) non-mucinous epithelial OC and an available FFPE tumor sample were eligible for GREAT and will be followed for up to 5 years. Genomic analyses were performed by 28 biological platforms coordinated at the national level with evaluation of HRD status (Myriad myChoice test, 95%) and of a gene tumor panel comprising BRCA1/2, RAD51C/D, FANCA, CDK12, NBN, ATM, CHEK2, BRIP1, PALB2, PlK3CA, ARID1A.ResultsFrom 12/2019 to 11/2022 a total of 1507 pts were included in GREAT by 94 French centers. Main clinical and tumor biological characteristics are reported in table 1. More than 1300 tumor samples have been already collected.ConclusionCharacteristics and treatment of the 1507 pts included in the real-life GREAT prospective study are representative of the standard AOC population. The clinically and biologically annotated GREAT cohort with collection of tumor samples offers a unique opportunity for evaluating new tumor targets for future drug development.DisclosuresCOI: Cf. attached.This study was partially funded by AstraZeneca.Abstract 350 Table 1GREAT cohort: Main clinical and tumor biological patient characteristics

PurposeBRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy.MethodsWe included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3–4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort).ResultsOverall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups.ConclusionsBRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

IntroductionRecently the PAOLA-1/ENGOT-ov25 phase-3 study (Ray-Coquard ESMO-2022) showed that the addition of olaparib maintenance to 1st-line platinum-based therapy and bevacizumab improved survival of advanced ovarian cancer (AOC) patients with HRD positive tumors independently of BRCA status (Myriad myChoice test). The aim of the European ENGOT initiative was to evaluate various academic HRD assays on PAOLA-1 tumor samples.MethodsThe novel HRD tests were initially assessed on 85 samples from PAOLA-1 BRCA-wild-type patients and results were correlated with Myriad test. Subsequently, >350 PAOLA-1 samples selected on the basis of tumor DNA availability were tested. Statistics were performed independently (v26.0-SPSS). The ability of each test to predict 1st-line olaparib maintenance efficacy versus placebo was evaluated on PAOLA-1 patient progression-free survival according to HRD/BRCA status.ResultsFrom 12/2019 to 09/2022 a total of 8 European academic laboratories representing 6 countries completed the clinical validation process on the PAOLA-1 samples. Despite the variety of methodological approaches and some differences in the distribution of HRD status, all of tests were clinically validated (table 1) and did not differ significantly from Myriad test results. Progression-free survival hazard ratio between olaparib and placebo arms depending on the assay was between 0.30 and 0.50 for HRD positive patients and between 0.88 and 1.15 for HRD negative patients.Abstract PO009/#424 Table 1HRD clinically validated tests from 8 academic laboratories and the reference myChoice Myriad HRD testConclusion/ImplicationsThe ENGOT HRD initiative is a unique collaboration of European academic laboratories involved in gynaecology oncology translational research. A total of 8 innovative HRD tests achieved a clinical validation from AOC tumor samples of the phase 3 PAOLA-1 study.

The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)—Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.