Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia

Despite recent progress in acute lymphoblastic leukemia (ALL) therapies, a significant subset of adult and pediatric ALL patients has a dismal prognosis. Better understanding of leukemogenesis and recognition of germline genetic changes may provide new tools for treating patients. Given that hematopoietic stem cell transplantation, often from a family member, is a major form of treatment in ALL, acknowledging the possibility of hereditary predisposition is of special importance. Reports of comprehensive germline analyses performed in adult ALL patients are scarce. Aiming at fulfilling this gap of knowledge, we investigated variants in 93 genes predisposing to hematologic malignancies and 70 other cancer-predisposing genes from exome data obtained from 61 adult and 87 pediatric ALL patients. Our results show that pathogenic (P) or likely pathogenic (LP) germline variants in genes associated with predisposition to ALL or other cancers are prevalent in ALL patients: 8% of adults and 11% of children. Comparison of P/LP germline variants in patients to population-matched controls (gnomAD Finns) revealed a 2.6-fold enrichment in ALL cases (CI 95% 1.5-4.2, p = 0.00071). Acknowledging inherited factors is crucial, especially when considering hematopoietic stem cell transplantation and planning post-therapy follow-up. Harmful germline variants may also predispose patients to excessive toxicity potentially compromising the outcome. We propose integrating germline genetics into precise ALL patient care and providing families genetic counseling.Peer reviewe

Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.Peer reviewe

Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.</p

Germline Genetics and Somatic Mutational Signatures in a Series of High-Risk Adult and Pediatric Acute Lymphoblastic Leukemia Patients

Akuuttiin lymfaattiseen leukemiaan (ALL) sairastuneiden ennuste on parantunut viimeisten vuosikymmenten aikana huomattavasti, mutta edelleen osa potilaista menestyy erittäin huonosti annetuista hoidoista huolimat-ta. Leukemiaa ei ole perinteisesti pidetty perinnöllisenä syöpäsairautena, mutta edeltävien vuosien aikana tieto geeniperimän vaikutuksesta leukemian syntyyn on lisääntynyt. Tutkimuksemme tavoitteena oli selvittää itura-tavarianttien esiintymistä akuutille lymfaattiselle leukemialle altistavissa geeneissä, löytää uusia leukemialle altistavia geenejä ja selvittää geeniperimän vaikutusta leukemian syntyyn. Tutkimukseen valittiin 115 korkean riskin leukemiapotilasta, josta aikuisia oli 49 ja lapsia 66. Käytössämme oli iho- tai verinäytteistä eristetystä DNA:sta tehdyn eksomisekvensoinnin data sekä potilaiden kliiniset tiedot potilastietojärjestelmistä. Tutkimuksessamme 6 %:lta (3/49) aikuispotilaista ja 11 %:lta (7/66) lapsipotilaista löytyi patogeeninen tai todennäköisesti patogeeninen variantti akuutille lymfaattiselle leukemialle altistavassa geenissä. Kun huomi-oidaan myös merkitykseltään epävarmat variantit, variantteja löytyi 20 %:lta (10/49) aikuispotilaista ja 15 %:lta (10/66) lapsipotilaista. Uusia potentiaalisia akuutille lymfaattiselle leukemialle altistavia geenejä löytyi neljä: APC, FGFR3, MUTYH ja MYH11. Leukemian syntyyn vaikuttavien mekanismien tutkimiseksi analysoi-tiin potilaiden somaattisten mutaatioita. Tässä analyysissa paljastui uusia piirteitä leukemiapotilaiden somaat-tisen mutaatioiden osalta sekä eroja lapsi- ja aikuispotilaiden välillä. Tutkimustulos osoittaa leukemialle altis-tavien ituratavarianttien esiintymisen merkittävällä osalla leukemiapotilaista, sekä korostaa geeniperimän tutkimisen merkitystä etenkin niillä leukemiapotilailla, joita hoidetaan kantasolusiirrolla sisarluovuttajalta

Robots are coming to town : A visual experiment on urban belonging and anxiety

Robots are becoming increasingly common in urban social environments and this is likely to cause emotional reactions among people. Utilizing theoretical frameworks of social identity approach and integrated threat theory, we investigated a sense of belonging to and perceived anxiety toward an urban environment with robots. We conducted a visual survey experiment using a representative sample of Finnish adults (N = 1226). Results based on multilevel regression analysis showed that, compared to deserted settings or settings with humans, robots in urban spaces decreased a sense of belonging to and increased anxiety toward an urban environment. Participants who were living in less urban areas, older, or neurotic reported a lower sense of belonging. Women and people that were living in less urban areas, young, neurotic, or introverted reported higher perceived anxiety. The results suggest that new technologies like robots in urban spaces can bring forth also feelings of anxiety and disruption for the sense of belonging, at least for some people. Hence, introduction of these technologies should be considered carefully in urban planning. Our study contributes to the theoretical discussions on place identity and examining anxiety as a disruption of the identification process.Peer reviewe

Z-scores for comparative analyses of spermatogonial numbers throughout human development

Objective: To normalize age-dependent effects on standardized measures of spermatogonial quantity such as the number of spermatogonia per tubular cross-section (S/T) or fertility index. Design: Published quantitative histologic data on human spermatogonial numbers were used to create Z-scores for reference means and tested on archived testicular tissue samples. Setting: Retrospective cohort study. Patient(s): The sample cohort comprised testicular samples from 24 boys with cancer diagnosis and 10 with Klinefelter syndrome, as part of the fertility preservation programs NORDFERTIL and Androprotect, as well as archived histologic samples from 35 prepubertal boys with acute lymphoblastic leukemia and 20 testicular biobank samples. Intervention(s): None. Main Outcome Measure(s): Z-score values for S/T and fertility index on the basis of morphology and germ cell-specific markers (MAGEA4 and/or DDX4) were calculated, and the impact of cancer therapy exposure and genetic disorders on Z-score values was evaluated. Result(s): The Z-scores for S/T values in the nontreated samples (-2.08 +/- 2.20, n = 28) and samples treated with nonalkylating agents (-1.90 +/- 2.60, n = 25) were comparable within +/- 3 standard deviations of the reference mean value but differed significantly from samples exposed to alkylating agents (-12.14 +/- 9.20, n = 22) and from patients with Klinefelter syndrome (-11.56 +/- 4.89, n = 8). The Z-scores for S/T were correlated with increasing cumulative exposure to alkylating agents (r = -0.7020). Conclusion(s): The Z-score values for S/T allow for the quantification of genetic and cancer treatment-related effects on testicular tissue stored for fertility preservation, facilitating their use for patient counseling. (C) 2021 by American Society for Reproductive Medicine.Peer reviewe