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Background: It has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC)., Methods: We performed whole-exome sequencing (WES) in 10 affected individuals from four families with at least three affected members. Polymerase chain reaction (PCR) and Sanger sequencing were performed to search for variants in the TINF2 gene in 40 FNMTC families. TINF2 transcripts and loss of heterozygosity (LOH) were studied in several affected patients of one family., Results: We found the c.507G>T variant in heterozygosis in the TINF2 gene in one family, co-segregating in all five affected members. This variant affects the normal splicing. LOH was not observed., Conclusions: Our results reinforce the TINF2 gene as a susceptibility cause of FNMTC suggesting the importance of location of frameshift variants in TINF2 . According to our data and previous literature, TINF2 pathogenic variants appear to be a significant risk factor for the development of NMTC and/or melanoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance., Methods: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi., Results: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively., Conclusions: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option., (© 2024. The Author(s).)

Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter ( k out ) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the k out determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the k out parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels., Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes., Results: Although differentially expressed mRNAs did not reach a significant adjusted p -value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling., Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aguado-Flor, Fuentes-Raspall, Gonzalo, Alonso, Ramón y Cajal, Fisas, Seoane, Sánchez-Pla, Giralt, Díez and Gutiérrez-Enríquez.)

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies., Significance: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin., (©2022 American Association for Cancer Research.)