Somatic Features Research Articles

On the a priori origin of creativity

Aim to explore the nature of creativity as a synergistic process.
 Creativity is a specific human activity presenting a complex configuration of all the personal abilities and characteristics such as sensual and emotional states, intellect, imagination, personal and social characteristics, somatic features and the situationality. But there must be something that transforms all this ontic multitude into an ontologically significant creative event. This something is an a priori form of sensibility spatium (by Deleuze), a sense of the intensity of depth and capacity of space, which, like an attractor, starts the process of crystallization of the work of art. Any creative action (accomplished experience) reveals the deep connections of this particular situation, given here and now. Accomplishment is the very intense interaction of the agent with the material, the exchange of energies between the acting person and the environment, the synergy of a person and the world, where spatium (intuition of the depth and vitality of the situation) plays the role of an attractor, forcing the variety merge into a whole.
 Results. The a priori ability to contemplate the whole (spatium), inherent in human sensibility, is realized in specific historical and specific cultural forms of art in different ways. The article outlines the history of such an implementation.

Long-term changes in physical fitness components determining the motor performance of young people studying physiotherapy in 2001–2020

The aim of the study is to assess changes in basic somatic features and motor components of physical fitness of physiotherapy students in the years 2001–2020. Hypotheses were made about the lack of a secular trend in body height and weight, the deterioration of motor efficiency and the lack of conditioning of the examined changes by social factors. Every year, students of physiotherapy at Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń (Poland) were examined in terms of height, weight, chest circumference, balance, speed, power, agility and endurance. The results were obtained from 1161 female students and 464 male students. There was weight gain in the group of women (R2 = 0.41, p = 0.00314), deterioration of speed (for women R2 = 0.579, p = 0.001; for men R2 = 0.301, p = 0.0185) and deterioration of power (for women R2 = 0.51, p = 0.001, p = 0.001; for men R2 = 0.0432, p = 0.00303). The stability of the remaining features was also found, as well as the lack of their conditioning by social factors. Predictors of maintaining motor fitness were identified, i.e. male gender, fitness exam qualifying for studies and chest circumference. The creation of conditions and requirements encouraging greater care for the appropriate level of motor fitness of people undertaking physiotherapy studies seems justified. This observation may apply to other academia providing training for the profession of physiotherapist.

The influence of pregnant women's physical activity on selected perinatal parameters

AIM OF THE PAPER: Evaluation of influence of physical activity on selected perinatal parameters. MATERIALS AND METHODS: The study included 300 women in physiological pregnancy. The group was divided to physical active and non-physical active women by KAPAS survey which they fill out retrospectively. Both groups were identical in counts. Selected perinatal parameters were monitored such as: increase of body mass, in which week the pregnancy ended, necessity of using induction labor or supply with synthetic oxytocin and crotch injuries. The respondents of both groups fill up the KAPAS questionnaire second time up to 7 days after labor to assess physical activity during pregnancy. RESULTS: Both groups were homogenic in terms of somatic features. Increase of body mass was statistically significant lover in group of physically active women compare to non-active women. Birth mass of infant was significantly higher in the group of physically non-active women. It was proved that there is significant differences in physical activity during pregnancy between both groups. There were dependency between age and delivery term in physically active women. There were strong relationship between week when the pregnancy ended and necessity of using induction labor in both groups. There were no relationship between supplying with synthetic oxytocin during labor, crotch injuries and physical activity. CONCLUSION: Physical activity during pregnancy decreased the percentage of labor with inductive delivery and prevents weight gain during pregnancy. Women that were active before pregnancy sustained there physical activity during pregnancy. Women that weren’t active before pregnancy also weren’t active during pregnancy. Physical activity have no relationship with crotch injury or necessity of using synthetic oxytocin during labor.

Frequency of iduronate-2-sulfatase gene variants detected in newborn screening for mucopolysaccharidosis type II in Japan

Mucopolysaccharidosis II (MPS II) is an X-linked, recessive, inborn metabolic disorder caused by defects in iduronate-2-sulfatase (IDS). The age at onset, disease severity, and rate of progression vary significantly among patients. This disease is classified into severe or mild forms depending on neurological symptom involvement. The severe form is associated with progressive cognitive decline while the mild form is predominantly associated with somatic features. Newborn screening (NBS) for MPS II has been performed since December 2016, mainly in Kyushu, Japan, where 197,700 newborns were screened using a fluorescence enzyme activity assay of dried blood spots. We diagnosed one newborn with MPS II with lower IDS activity, elevated urinary glycosaminoglycans, and a novel variant of the IDS gene. In the future, NBS for MPS II is expected to be performed in many regions of Japan and will contribute to the detection of more patients with MPS II, which is crucial to the early treatment of the disorder.

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.

CTNNB1 [OMIM *116806] encodes β-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.

Karadenizia, a new monospecific pachyiuline genus (Diplopoda: Julida: Julidae) from Turkey.

The present paper is dedicated to the description of the monospecific pachyiuline genus Karadenizia gen. nov. with the type species K. merti sp. nov. from Erçek Cave near the southern coast of the Black Sea in Turkey. In addition to the diagnosis and detailed description, brief notes on the locality and known ecology of this taxon are given. The relationship of this genus with some other pachyiulines is discussed based on the structure of the gonopods and some somatic features. The interesting colouration of the new taxon allows a brief discussion and hypothesis on the possible defensive role of such a colour pattern, which is also known in some other millipedes.

Reference Ranges and Development Patterns of Fetal Myocardial Function Using Speckle Tracking Echocardiography in Healthy Fetuses at 17 to 24 Weeks of Gestation.

The purposes of the study were to develop reference ranges and maturation patterns of fetal cardiac function parameters measured by speckle tracking echocardiography (STE) using multiple biometric variables at 17 to 24 weeks' gestation among Thai fetuses and to compare with other previous reports. The four-chamber view of the fetal heart in 79 healthy fetuses was suitably analyzed by STE to establish the best-fit regression model. The 95% reference intervals and Z-score equations of fetal cardiac function parameters were computed. The fractional area change of both ventricles, left ventricular (LV) end-diastolic and end-systolic volumes, LV stroke volume, LV cardiac output (CO), and LV CO per kilogram were all increased according to gestational age (GA) and five fetal biometric measurements. However, the global longitudinal strain, basal-apical length fractional shortening (BAL-FS), BAL annular free wall and septal wall FS, BAL free wall and septal wall annular plane systolic excursions, 24-segment transverse width FS, as well as LV ejection fraction were all independent of GA or other somatic characteristics. There were varying development patterns between fetal right and left ventricles of these cardiac function indices across the gestation period. Our study created Z-score and corresponding centile calculators, 5th and 95th centile reference tables, and corresponding graphs and determined the normal evolution across gestation using multiple somatic growth and age variables between 17 and 24 gestational weeks. These nomograms serve as an essential prerequisite for quantitatively evaluating fetal cardiac contractility and allow for precisely detecting early changes in the fetal heart function. · Most fetal cardiac function measurements were correlated with all the independent variables.. · Fetal ventricular function parameters have their own characteristic maturation changes.. · Racial variability may not occupy an important place for fetal myocardial function during these GA..

Multiple embodiment relations: sense-making in dissociative experiences

ABSTRACT In response to a call for new conceptualizations of the self that avoid mind/body dualisms, recent research has introduced more flexible and fluid theorizations of personhood. This paper takes a phenomenological approach to examine the perceived shifts in body ownership and distribution of agency which underpin such theorizations. We focus on two dissociative experiences, namely, spirit possession and virtual reality, explicating how consumers can experience changes of perspective by disconnecting from the mainstream of their conscious awareness, allowing for a controlled “letting go,” resulting in therapeutic gains. We highlight how consumers create a larger assemblage of the self beyond single viewpoints for a new kind of experiencing. We argue that existing work has treated embodiment in a fairly symmetrical manner, insufficiently considering the inherently somatic characteristics of consumer experiences as an articulation of a multiplicity and distribution of embodiment and agentic relations, both human and non-human.

Associations between common mental disorders and menopause: cross-sectional analysis of the 2014 Adult Psychiatric Morbidity Survey.

We investigated whether women who participated in a household survey in England were more likely to screen positive for possible generalised anxiety disorder and depression during and after menopause. We used logistic regression in secondary cross-sectional analyses of 1413 participants from the 2014 Adult Psychiatric Morbidity Survey data, adjusting for potential confounders (including age, deprivation score and chronic disease).We found that participants who were post-menopausal were more likely to screen positive for possible depression compared with participants who were pre-menopausal (3.9% v. 1.7%; adjusted odds ratio 3.91, 95% CI 1.23-12.46), but there was no association with perimenopause. We found no evidence of an association between menopausal stage and possible generalised anxiety disorder or symptom score. Clinicians should be aware of the association between menopause and depression, to best support women. Future research could focus on to what extent associations are driven by somatic features, and how this might be modified.

Four new species of mygalomorph spiders (Araneae, Halonoproctidae and Theraphosidae) from the Colombian Pacific region (Bahía Solano, Chocó).

The Colombian Pacific coast is an amazing natural region, immersed in one of the most unknown biodiversity hotspots in the world. An expedition carried out in the north of this area, at the Jardín Botánico del Pacífico (JBP) in Bahía Solano, Chocó, focused on studying the diversity of the mygalomorph spider fauna, allowed us to discover four new species included in the families Halonoproctidae and Theraphosidae. The trapdoor species Ummidiasolanasp. nov., and the theraphosids species Euthycaeluscunampiasp. nov. (Schismatothelinae), Melloinapacificasp. nov. (Glabropelmatinae), and Neischnocolusmecanasp. nov. (Theraphosinae) are illustrated, diagnosed, and described in detail. Photographs of somatic features and copulatory organs and a distribution map are provided. Morphological, taxonomical, and biogeographical aspects are discussed for each species. All these taxonomic novelties represent the first records of these genera for the region, expanding the range of geographic distribution of each of them. This work constitutes the first effort focused on characterizing the community of Mygalomorphae species in the Chocó Biogeographic Region.

A newly recorded genus with description of a new cave-dwelling species of Flagelliphantes (Araneae, Linyphiidae) from northeastern China.

The genus Flagelliphantes Saaristo & Tanasevitch, 1996 was proposed by Saaristo & Tanasevitch, 1996 to accommodate three ex-Lepthyphantes species distributed in northern Eurasia. Male Flagelliphantes are easlily recognised by having a hood-shaped thumb on the embolus. The females have a long, S-shaped scape and the posterior median plate of the epigyne is grossly enlarged ("hypertrophied"). While examining Linyphiidae Blackwall, 1859 specimens from Yunxia Cave in China's Jilin Province, we discovered a new cave-dwelling species of the genus Flagelliphantes, F.yunxia sp. n. In this paper, we provide detailed description and photos of its diagnostic somatic and genitalic features. It is the first record of the genus from China.

Two new species of the sac-spider genus Clubiona Latreille, 1804 (Araneae, Clubionidae) and the female of C. subcylindrata from China

Two new species of the genus Clubiona Latreille, 1804 are described: C. tianpingshan sp. nov. (♂♀) and C. flammaforma sp. nov. (♂♀) from central and south China. The female of C. subcylindrata Wang et al., 2018 is described for the first time. Detailed descriptions, photographs of somatic features and copulatory organs, as well as a distribution map of these three species, are provided.

“I’m Told I Don’t Look Like a Foreigner”: Everyday Racism in Contemporary Italy

In our article, we aim to explore the experience of everyday racism of young people with migrant parents in Italy. Drawing on the analysis of 20 interviews, we seek to reconstruct the overall dynamics of racial microaggressions, highlighting how the context in which microaggressions occur and the interplay between ethnic background, gender, and somatic features influences the interpretations and reactions of the victims. We highlight the boundary work and identity negotiation process carried out in everyday encounters. We also show that participants’ experience oscillates between the claim of not-taken‐for‐granted citizenship, the feeling of being confined within ethno‐cultural imaginaries, and the experience of overt manifestations of racism. Finally, we highlight both the process by which victims come to recognise racial microaggressions and the obstacles they face in coping with them.

Abstract 5429: Using machine learning to predict tissue of origin from somatic mutation features

Abstract Background: Predicting tissue of origin (ToO) using clinical and molecular data improves diagnostic accuracy up to 95% in patients with Cancer of Unknown Primary (CUP). It is hypothesized that better treatment stratification of CUP patients using omics and machine learning (ML) classifiers may improve prognosis. Methods: We used publicly available whole exome somatic mutation data from 4733 primary solid tissue samples, across 11 tumor types from the TCGA database, and employed a ML classifier to predict their ToO. We used 5 sets of modeling features: 1) Non-silent somatic mutation burden of 230 cancer-related genes 2) Frequency of SNP substitution type 3) Trinucleotide mutation frequency 4) Copy number variation of the 230 cancer-related genes 5) Presence of hotspot mutations. We trained a Support Vector Machine on a training subset (80% of samples) and tuned the hyperparameters maximizing a 5-fold cross-validation F1-score. We then tested the model performance on a validation subset (20% of samples) and on a limited (n=6) dataset of metastatic samples present in the TCGA database. Results: On the primary tumor validation set, we achieved an average AUC of 0.98(std: 0.02) and top 1, top 2 and top 3 accuracies of 80%(std: 0.11), 90%(std: 0.08) and 95%(std: 0.04) respectively, across 11 tumor types. The classification accuracy plateaus after ~300 samples, suggesting further data collection may benefit low performing tumor types. The 2 worst performers: esophageal and stomach cancers were mostly misclassified with colorectal cancers, reflecting their relative similarity. On metastatic samples (n=6) the model achieved a 67% accuracy, this is work in progress. Conclusion: Our study confirms the potential for a DNA-based machine learning approach to improve prognosis in CUP patients by aiding diagnosis of ToO. To this end, we plan to take this study further by applying this approach to large, independent datasets derived from metastatic samples and liquid biopsies from CUP patient cohorts. Table 1. Top_1_acc Top_2_acc Top_3_acc Precision Recall F1_score Training_size Breast 0.88 0.97 0.99 0.88 0.84 0.86 756 Colorectal 0.85 0.97 0.98 0.83 0.83 0.83 460 Oesophagus 0.5 0.75 0.89 0.51 0.5 0.51 144 Liver 0.83 0.92 0.96 0.82 0.89 0.85 288 Lung 0.86 0.91 0.94 0.98 0.81 0.88 396 Ovary 0.87 0.94 0.97 0.77 0.9 0.83 312 Pancreas 0.73 0.79 0.85 0.62 0.7 0.66 132 Prostate 0.88 0.94 0.98 0.75 0.88 0.81 380 Sarcoma 0.78 0.84 0.96 0.8 0.82 0.81 180 Stomach 0.73 0.91 0.95 0.68 0.58 0.62 340 Endometrial 0.9 0.97 0.99 0.86 0.87 0.87 400 Mean 80.09% 90.09% 95.09% 0.77 0.78 0.78 344 Top_1_acc_n Top_2_acc_n Top_3_acc_n n samples Metastatic breast 2 2 2 2 Metastatic prostate 0 0 0 1 Metastatic pancreas 0 0 0 1 Metastatic sarcoma 1 1 1 1 Metastatic oesophagus 1 1 1 1 Mean accuracy 67% 67% 67% Citation Format: Andrea Giorni, Prabu Sivasubramiam, Aidan Kubeyev, Jordan Laurie, Luiz Silva, Matthew Foster, Uzma Asghar, Matthew Griffiths. Using machine learning to predict tissue of origin from somatic mutation features. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5429.

DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer

BackgroundFew studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong.MethodsWe performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath’s pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson’s correlation (r), Kruskal–Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors.ResultsDNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e−16) than in tumor tissue (Pearson r = 0.31, P = 7.8e−06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e−06) and PGR (Pearson r = 0.36, P = 2.4e−05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA.ConclusionsOur findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.

One new genus and nine new species of Linyphiidae spiders from Yintiaoling Nature Reserve, Chongqing of China

One new genus and nine new species of Linyphiidae are described here from Yintiaoling Nature Reserve (YNR), Chongqing of China as: Caracladus daguanshanensis sp. n. (both sexes), Centromerus alatus sp. n. (male only), Dicristatus modaoxiensis sp. n. (both sexes), Hypselistes arcus sp. n. (male and female), Ryojius flosculus sp. n. (male only), R. latus sp. n. (male only), Shaanxinus shizhuziensis sp. n. (both sexes), Sinogone caesuma gen. & sp. n. (both sexes), and Walckenaeria hongqiensis sp. n. (both sexes). Detailed descriptions, photographs of genital characters and somatic features are presented.

Relationships between selected indices of postural stability and sports performance in elite badminton players: Pilot study.

The main aim of this study was to determine the relationships between postural stability and the place in the ranking of badminton players. The study examined 10 elite players from Polish national badminton team. The scope of the study included basic somatic characteristics, such as body height, body weight, BMI, and training experience. A Microgate GYKO inertial sensor system was used to assess the postural stability of athletes. Using Spearman's rank correlation, cause-and-effect relationships between the place in the sports ranking and the analyzed variables characterizing postural stability were recognized. Depending on the distribution and homogeneity of variance, the significance of differences in variables that characterize postural stability between players of different sports skill levels (two groups) was calculated. The Student's t-test or Mann-Whitney's U-test was used for this purpose. In general, the athletes with higher positions on the ranking list presented a higher level of postural stability in both tests, which is also confirmed by the normalized values. However, for all variables of postural stability, no statistically significant correlations with sports ranking were observed. Higher values of Spearman's rank correlation coefficients were found for the test performed in the one-foot standing test compared to the two-foot test. The results obtained indicate that particular attention in badminton training should be paid to the development of the level of postural stability in order to improve sports performance.

A generalizable machine learning framework for classifying DNA repair defects using ctDNA exomes

Specific classes of DNA damage repair (DDR) defect can drive sensitivity to emerging therapies for metastatic prostate cancer. However, biomarker approaches based on DDR gene sequencing do not accurately predict DDR deficiency or treatment benefit. Somatic alteration signatures may identify DDR deficiency but historically require whole-genome sequencing of tumour tissue. We assembled whole-exome sequencing data for 155 high ctDNA fraction plasma cell-free DNA and matched leukocyte DNA samples from patients with metastatic prostate or bladder cancer. Labels for DDR gene alterations were established using deep targeted sequencing. Per sample mutation and copy number features were used to train XGBoost ensemble models. Naive somatic features and trinucleotide signatures were associated with specific DDR gene alterations but insufficient to resolve each class. Conversely, XGBoost-derived models showed strong performance including an area under the curve of 0.99, 0.99 and 1.00 for identifying BRCA2, CDK12, and mismatch repair deficiency in metastatic prostate cancer. Our machine learning approach re-classified several samples exhibiting genomic features inconsistent with original labels, identified a metastatic bladder cancer sample with a homozygous BRCA2 copy loss, and outperformed an existing exome-based classifier for BRCA2 deficiency. We present DARC Sign (DnA Repair Classification SIGNatures); a public machine learning tool leveraging clinically-practical liquid biopsy specimens for simultaneously identifying multiple types of metastatic prostate cancer DDR deficiencies. We posit that it will be useful for understanding differential responses to DDR-directed therapies in ongoing clinical trials and may ultimately enable prospective identification of prostate cancers with phenotypic evidence of DDR deficiency.

Suicide risk among residents in a cross-sectional study: the role of the Interpersonal Psychological Theory of Suicide

IntroductionThe peculiar requests of postgraduate teaching could affect the students’ lives, predisposing them to mental disorders and suicide risk (e.g. Abreu et al., 2021). The Interpersonal Psychological Theory of Suicide (IPTS) (Joiner, 2005) is a model that has proved useful in explaining this risk.ObjectivesWe analyzed risk factors associated with current suicidal ideation (SI) and history of suicidal planning and/or suicide attempt (SP/SA) in a sample of 97 Italian residents in psychological (n= 17, 17.5%) and medical and health care area (n=80, 82.5%) (mean age 29.18±3.25 SD).MethodsSocio-demographic, psychological (i.e. State-Trait Anxiety Inventory, Beck Depression Inventory – II; BDI-II, Rosenberg Self-Esteem Scale, Reasons For Living Inventory; RFL, Psychache Scale, Mental pain questionnaire; MPQ, Visual Analogue Scale - VAS - on mental pain, Acquired Capability for Suicide Scale-Fearlessness About Death) psychosocial (i.e. Interpersonal Needs Questionnaire; INQ, UCLA Loneliness Scale Version 3, Multidimensional Scale of Perceived Social Support; MSPSS) and somatic pain features (i.e. VAS, Pain Vigilance and Awareness Questionnaire; Self-Awareness Questionnaire; SAQ) were collected through an online questionnaire. We compared residents with SI vs No SI and residents with SP/SA vs No SP/SA and the emerged significant variables, have been inserted in logistic regression models with stepwise method, backward elimination.ResultsThe presence of depression (BDI-II), low reasons for living (RFL), psychological pain (Psychache Scale and MPQ), interoceptive awareness (SAQ), Thwarted Belongingness (TB, INQ subscale), loneliness (UCLA) and low perceived social support (MSPSS) were associated with both current SI and history of SP/SA. Concerning regression models, TB (INQ) increased the likelihood of SI while Survival and Coping Beliefs (RFL subscale) reduced it. The model explained 49% of the variance of SI by correctly predicting 88.7% of SI cases. Perceived social support (MSPSS)reduced the likelihood of current SP/SA levels while interoceptive awareness (SAQ) increased it. This model explained 40% of the variance of SP/SA by correctly predicting 82.5% of suicide risk cases.ConclusionsWe have identified risk and protective factors for suicide, consistent with the IPTS, which can orient the prevention, evaluation and clinical treatment of residents.Disclosure of InterestNone Declared

Abstract PD14-03: PD14-03 Reappraising the Fanconi Anemia DNA repair pathway in breast cancer risk and precision intervention: Insights and opportunities from the City of Hope INSPIRE study

Abstract Background: Fanconi Anemia (FA) proteins facilitate homologous recombination (HR)-mediated repair of DNA interstrand cross-links. Germline monoallelic, pathogenic/likely pathogenic (P/LP) variants in the highly-penetrant (HP) breast cancer (BC) FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN)), compromise HR and predispose to hereditary BC. The effects of monoallelic, pathogenic variants in other non-HP BC FA genes upon HR and BC predisposition remain less understood. In this investigation we report the germline mutational landscape of FA gene P/LP variants and somatic molecular consequences of patients with BC diagnoses from City of Hope’s (COH) INSPIRE (Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation) study. Methods: COH-INSPIRE is a universal access study open to all patients at COH with a personal and/or family history of cancer. Patients undergo custom panel-based germline genetic testing to detect P/LP single nucleotide variants (SNVs), short insertions/deletions (indels) and exon-level deletions/duplications in 155 cancer-predisposition genes including the HP BC FA genes and 15 non-HP BC FA genes [FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2)]. Patients’ tumor specimens undergo somatic tumor (&amp;gt;400X)-normal (&amp;gt;180X) whole exome and transcriptome sequencing (&amp;gt;50 million reads). Somatic sequencing identifies P/LP SNVs, indels, copy number events, and fusions. Secondary analyses assessed somatic homologous recombination deficiency (HRD) by examining tumor mutational signatures, as well as an ensemble HRD score derived by combining individual genomic loss of heterozygosity, telomeric allelic imbalance and large-scale molecular transition scores. Reference comparison of germline and somatic features to current FDA therapeutic guidelines and NIH clinical trials registrations determined eligibility for precision therapeutic intervention and clinical trial enrollment. Results: Of 7,584 patients enrolled in COH-INSPIRE, 1,651 (21.8%) patients had a BC diagnosis. Germline panel testing of BC patients identified 204 (12.4%) with germline P/LP variant in a FA gene. Greater than one third of FA gene-altered BC patients (37.7%) carried a P/LP variant in a non-HP BC FA gene. We observed that BC patients with a non-HP BC FA gene variant may demonstrate HR compromise as evidenced by presence of a Signature 3 mutational profile or an elevated combined HRD score (&amp;gt; 33 and/or &amp;gt; 42). (Table 1) Further, we identified ostensible segregation of triple negative BC in a family harboring a germline pathogenic variant in FANCG. With regard to precision clinical actionability (i.e. qualification for targeted therapeutic intervention [PARP inhibitor (PARPi)] and/or clinical trial) for patients with advanced stage BC: All patients with germline P/LP HP BC FA gene variant and 20.7% (N=16) of patients with a P/LP FA non-HPBC FA gene variant met criteria for treatment with on/off-label PARPi. 100% of patients with advanced BC with germline P/LP HP BC or non-HPBC FA gene variant qualified for a clinical trial. Conclusions: Patients with BC often carry a germline monoallelic, P/LP FA gene variant; in more than one third, the FA gene alteration occurs in a non-HP BC FA gene. BC patients harboring a monoallelic germline non-HP BC P/LP FA gene may exhibit somatic mutational signatures and HRD scoring consistent with compromise of HR. Somatic tumor evaluation of BC patients with germline P/LP non-HP BC FA gene variants expands opportunities for precision therapeutic intervention and clinical trial enrollment. Continued appraisal will clarify emerging questions of germline non-HP P/LP FA gene-associated autosomal dominant BC risk and management as well as facilitate optimization of precision BC care. Table 1 Summary Molecular Features of BC patients with P/LP Variants in FA gene from COH-INSPIRE Citation Format: Laura Kruper, Kevin McDonnell, Joseph Bonner, Kevin K. Tsang, Veronica Jones, Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Heather Hampel, Wai Park, Gregory E. Idos, Stacy Gray, Stephen Gruber. PD14-03 Reappraising the Fanconi Anemia DNA repair pathway in breast cancer risk and precision intervention: Insights and opportunities from the City of Hope INSPIRE study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-03.