Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

Mortality risk among Autistic children and young people: A nationwide birth cohort study.

LAY ABSTRACT: Existing literature indicates that Autistic people have shorter life expectancy, but little is known about the mortality risk among Autistic children and young people (0-24 years). We used a 15-year nationwide birth cohort study to estimate the mortality risk among Autistic children and young people in Aotearoa/New Zealand. The study included 895,707 children and 11,919 (1.4%) were Autistic. We found that autism was associated with a significantly higher mortality risk compared to the non-Autistic population. In addition, we found that this risk was significantly higher among females compared to males and for those with a co-occurring intellectual disability. Increased efforts are required to better meet the health needs of this population.

Associations between type 1 diabetes and educational outcomes: an Aotearoa/New Zealand nationwide birth cohort study using the Integrated Data Infrastructure.

AIMS/HYPOTHESIS: Type 1 diabetes is one of the most common chronic diseases of childhood. It is hypothesised that the metabolic and psychosocial consequences of type 1 diabetes may affect educational outcomes; however, existing literature presents conflicting results. This study aimed to assess whether educational outcomes differ for young people with and without type 1 diabetes in Aotearoa/New Zealand (NZ). METHODS: This was a nationwide 9 year birth cohort study of all people born in NZ from 1993 to 2001 using linked administrative data held within the Integrated Data Infrastructure, a national research database containing linked health and non-health data. Educational outcomes of high school attainment, high school attendance and university enrolment were measured from age 13 years until 20 years. Generalised linear regression models with log link and Gaussian distributions were used to compare educational outcomes between those with and those without type 1 diabetes, adjusting for sociodemographic and maternal characteristics. RESULTS: Of the 442,320 children in the birth cohort, type 1 diabetes was identified in 2058 (0.47%) (mean [SD] age of type 1 diabetes diagnosis 7.7 [3.4] years). Educational outcomes were significantly lower for children with type 1 diabetes than for those without type 1 diabetes, including for any high school qualification (RR 0.97 [95% CI 0.95, 0.99]), university entrance-level high school attainment (RR 0.88 [95% CI 0.84, 0.92]), regular high school attendance (RR 0.91 [95% CI 0.85, 0.97]) and university enrolment (RR 0.93 [95% CI 0.88, 0.98]), even after adjusting for sociodemographic and maternal factors. In addition, educational outcomes were substantially lower for those with post type 1 diabetes diagnosis hospitalisations for diabetic ketoacidosis and hypoglycaemia. CONCLUSIONS/INTERPRETATION: In this whole NZ birth cohort study, type 1 diabetes was associated with lower educational outcomes spanning secondary school and into university enrolment. Ongoing efforts to support students with type 1 diabetes are needed, particularly for those with a greater risk profile.

Rapid infant weight gain or point-in-time weight status: Which is the best predictor of later obesity and body composition?

OBJECTIVE: The aim of this study was to determine which growth indicator (weight, weight-for-length, BMI) and time frame (6- or 12-month intervals between 0 and 24 months) of rapid infant weight gain (RIWG) best predicted obesity risk and body composition at 11 years of age. METHODS: RIWG (increase ≥0.67 z scores between two time points) was calculated from weight and length/height at birth, 0.5, 1, 1.5, and 2 years. The predictive value of each measure and time frame was calculated in relation to obesity (BMI ≥95th percentile) and body fat (fat mass index [FMI], dual-energy X-ray absorptiometry scan) at 11 years. RESULTS: The sensitivity (1.5% to 62.1%) and positive predictive value (12.5% to 33.3%) of RIWG to predict obesity varied considerably. Having obesity at any time point appeared a stronger risk factor than any indicator of RIWG for obesity at 11 years. Obesity at any age during infancy consistently predicted a greater FMI of around 1.1 to 1.5 kg/m2 at 11 years, whereas differences for RIWG were inconsistent. CONCLUSIONS: A simple measure of obesity status at a single time point between 6 and 24 months of age appeared a stronger risk factor for later obesity and FMI than RIWG assessed by any indicator, over any time frame.

Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.

PURPOSE: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. METHODS: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. RESULTS: We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias. CONCLUSION: Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.

Identifying neurodevelopmental disabilities from nationalised preschool health check.

OBJECTIVE: Models of psychometric screening to identify individuals with neurodevelopmental disabilities (NDDs) have had limited success. In Aotearoa/New Zealand, routine developmental surveillance of preschool children is undertaken using the Before School Check (B4SC), which includes psychometric and physical health screening instruments. This study aimed to determine whether combining multiple screening measures could improve the prediction of NDDs. METHODS: Linked administrative health data were used to identify NDDs, including attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disability, within a multi-year national cohort of children who undertook the B4SC. Cox proportional hazards models, with different combinations of potential predictors, were used to predict onset of a NDD. Harrell's c-statistic for composite models were compared with a model representing recommended cutoff psychometric scores for referral in New Zealand. RESULTS: Data were examined for 287,754 children, and NDDs were identified in 10,953 (3.8%). The best-performing composite model combining the Strengths and Difficulties Questionnaire, the Parental Evaluation of Developmental Status, vision screening and biological sex had 'excellent' predictive power (C-statistic: 0.83) compared with existing referral pathways which had 'poor' predictive power (C-statistic: 0.68). In addition, the composite model was able to improve the sensitivity of NDD diagnosis detection by 13% without any reduction in specificity. CONCLUSIONS: Combination of B4SC screening measures using composite modelling could lead to significantly improved identification of preschool children with NDDs when compared with surveillance that rely on individual psychometric test results alone. This may optimise access to academic, personal and family support for children with NDDs.

Prevalence of low and high BMI during the first 3 years of life: using New Zealand national electronic health data.

BACKGROUND: Data on body mass index (BMI) in infants and toddlers worldwide are lacking, relative to older age groups. OBJECTIVES: To describe the growth (weight, length/height, head circumference, and BMI z-score) of New Zealand children under the age of 3 years, and examine differences by sociodemographic characteristics (sex, ethnicity, and deprivation). METHODS: Electronic health data were collected by Whanau Awhina Plunket, who provide free 'Well Child' services for approximately 85% of newborn babies in New Zealand. Data from children under the age of 3, who had their weight and length/height measured between 2017 and 2019, were included. The prevalence of BMI (WHO child growth standards) ≤2nd, ≥85th, and ≥95th percentiles were determined. RESULTS: Between 12 weeks and 27 months of age, the percentage of infants ≥85th BMI percentile increased from 10.8% (95% CI, 10.4%-11.2%) to 35.0% (34.2%-35.9%). The percentage of infants with high BMI (≥95th percentile) also increased, particularly between 6 months (6.4%; 95% CI, 6.0%-6.7%) and 27 months (16.4%; 15.8%-17.1%). By contrast, the percentage of infants with low BMI (≤2nd percentile) appeared steady between 6 weeks and 6 months, and declined at older ages. The prevalence of infants with a high BMI appears to increase substantially from 6 months across sociodemographic characteristics, with a widening prevalence gap by ethnicity occurring from 6 months, mirroring that of infants with a low BMI. CONCLUSIONS: The number of children with high BMI increases rapidly between 6 months and 27 months of age, suggesting this is an important timeframe for monitoring and preventive action. Future work should investigate the longitudinal growth trajectories of these children to determine if any particular patterns predict later obesity and what strategies could effectively change them.

Regional variation in sudden unexpected death in infancy in New Zealand.

AIM: To estimate the relative risk of sudden unexpected death in infancy (SUDI) by district health board (DHB) in New Zealand after adjustment for socio-economic deprivation, ethnicity and other demographic factors. METHODS: We conducted a population-based cohort study using data from the Integrated Data Infrastructure, a large research database containing linked data from a range of government agencies. The study population was all live births and their mothers in New Zealand from 2012 to 2018. The exposure of interest was DHB. The outcome was SUDI. RESULTS: There were 418 068 live births in New Zealand from 2012 to 2018, and of these 415 401 (99.4%) had valid DHB data. There was considerable variation in the proportion of infants in each DHB living in the most deprived decile varying from 4.5% in Nelson, West Coast and Canterbury to 29.7% in Counties Manukau. There were 267 SUDI cases, giving an overall rate of 0.64/1000 live births during the study period (2012-2018). The SUDI rate varied from 1.11/1000 in Northland to 0.30/1000 in Waitemata and Auckland. Counties Manukau had the largest number of deaths (n = 54; rate = 1.08/1000). Five DHB regions had increased risk of SUDI compared to the reference group but, after adjustment, no DHB was significantly increased. CONCLUSIONS: This study found that there is marked variation in SUDI risk by DHB, but this is explained by socio-economic and demographic variation within DHBs. This study emphasises the importance of the contribution of social determinants of health to SUDI.

Is the cost-effectiveness of an early-childhood sleep intervention to prevent obesity affected by socioeconomic position?

OBJECTIVE: This study aimed to determine whether the cost-effectiveness of an infant sleep intervention from the Prevention of Overweight in Infancy (POI) trial was influenced by socioeconomic position (SEP). METHODS: An SEP-specific economic evaluation of the sleep intervention was conducted. SEP-specific intervention costs and effects at age 5 years, derived from the trial data, were applied to a representative cohort of 4,898 4- to 5-year-old Australian children. Quality-adjusted life years and health care costs were simulated until age 17 years using a purpose-built SEP-specific model. Incremental cost-effectiveness ratios and acceptability curves were derived for each SEP group. RESULTS: The incremental cost-effectiveness ratios, in Australian dollars per quality-adjusted life year gained, were smaller in the low- ($23,010) and mid-SEP ($18,206) groups compared with the high-SEP group ($31,981). The probability that the intervention was cost-effective was very high in the low- and mid-SEP groups (92%-100%) and moderately high in the high-SEP group (79%). CONCLUSIONS: An infant sleep intervention is more cost-effective in low- and mid-SEP groups compared with high-SEP groups. Targeting this intervention to low-SEP groups would not require trade-offs between efficiency and equity.

The care of infants with rapid weight gain: Should we be doing more?

Rapid weight gain (RWG) during infancy is a known risk factor for later childhood obesity. It can be measured using a range of definitions across various time periods in the first 2 years of life. In recent years, some early childhood obesity prevention trials have included a focus on preventing RWG during infancy, with modest success. Overall, RWG during infancy remains common, yet little work has examined whether infants with this growth pattern should receive additional care when it is identified in health-care settings. In this viewpoint, we contend that RWG during infancy should be routinely screened for in health-care settings, and when identified, viewed as an opportunity for health-care professionals to instigate non-stigmatising discussions with families about RWG and general healthy practices for their infants. If families wish to engage, we suggest that six topics from early life obesity prevention studies (breastfeeding, formula feeding, complementary feeding, sleep, responsive parenting, and education around growth charts and monitoring) could form the foundations of conversations to help them establish and maintain healthy habits to support their infant's health and well-being and potentially lower the risk of later obesity. However, further work is needed to develop definitive guidelines in this area, and to address other gaps in the literature, such as the current lack of a standardised definition for RWG during infancy and a clear understanding of the time points over which it should be measured.

Launching an innovative educational model addressing substance use disorders and dental pain management (Project ECHO® in dentistry).

BACKGROUND: Uninformed opioid prescribing by dentists has contributed to the current opioid crisis. This report describes the development and implementation of an innovative, interactive, multidisciplinary, and participant-centric telementoring program "Pain Management and Substance Use Disorders Dental ECHO (Extension for Community Health Care Outcomes)". We disseminated information to dentists about appropriate opioid prescribing practices and engaged them with a focus on pain management and substance use disorders. The objective of this study was to assess the effectiveness of this program for self-reported: (1) change in knowledge and confidence related to clinical skills for dental pain management of patients with substance use disorders; (2) change in clinical behavior of dentists for safe opioids prescribing; and (3) change in clinic policies regarding safe opioids prescribing. METHODS: An interdisciplinary panel of experts in medicine, pharmacy, social work, and dentistry designed and led the "Pain Management and Substance Use Disorders Dental ECHO" for invited dental care providers and dental students. Six cohorts each consisting of six, 1-h-long sessions were conducted via the Zoom videoconference platform in years 2020 and 2021. Each session included a didactic expert presentation, a participant-presented patient case and discussion. Each participant completed pre- and post-program surveys to assess the program's influence on participant knowledge, clinical confidence and behavior change. RESULTS: The participants (N = 151) were dentists (n = 109), dental faculty (n = 15), dental residents (n = 6), dental hygienists/assistants (n = 13) and nurses and clinic administrators (n = 8). Self-reported perceived medication knowledge, confidence in identification, treatment and willingness to engage with substance use disorders patients, and reported compliance with Prescription Drug Monitoring Program (PDMP) checks increased significantly from before to after the sessions (p < 0.001). Overall, participants expressed high levels of satisfaction with the content and reported that the sessions provided high benefit. CONCLUSION: The Project ECHO model is effective in rapidly disseminating evidence-based information. Dentists viewed this model as having a high degree of benefit for the optimal management of dental pain and the recognition and treatment of substance use disorders.

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

Association Between High-Need Education-Based Funding and School Suspension Rates for Autistic Students in New Zealand.

Importance: Autistic students often experience poor educational outcomes that have implications for later life, including unemployment, interactions with the criminal justice system, increased risk for substance abuse, and low socioeconomic status. Improving educational outcomes is critical for ensuring that autistic young people can reach their potential. Objective: To quantify differences in suspension rates between autistic and nonautistic students and to assess whether high-need education-based funding for autistic students is associated with reduced rates of school suspension. Design, Setting, and Participants: This national cohort study used linked health and education data from New Zealand's Integrated Data Infrastructure. Data were obtained for students aged 5 to 16 years from January 1 to December 31, 2018, and analyzed July 7, 2021, to January 1, 2022. A novel case identification method was used to identify autistic students. Exposures: High-need education-based funding (Ongoing Resourcing Scheme [ORS]) obtained before 2019. Main Outcomes and Measures: Rates of suspension from school. Crude and adjusted analyses of the association between suspension rates and autism among the full population with adjustment made for sociodemographic characteristics (sex, age, ethnicity, deprivation, and urban or rural profile of residence) were conducted using complete-case, 2-level random intercept logistic multivariable regressions. To assess the association between ORS funding and suspension, analysis was restricted to autistic students. Results: Of the 736 911 students in the study population, 9741 (1.3%) were identified as autistic (median [SD] age, 10 [3.2] years; 7710 [79.1%] boys), and 727 170 (98.7%) as nonautistic (median [SD] age, 10 [3.4] years; 369 777 [50.9%] boys). School suspension was experienced by 504 autistic students (5.2%) and 13 845 nonautistic students (1.9%). After adjustment for demographic characteristics, autistic students had significantly higher odds of suspension than their nonautistic peers (adjusted odds ratio, 2.81; 95% CI, 2.55-3.11). Of the 9741 autistic students, 2895 (29.7%) received high-need education-based (ORS) funding. Suspensions were experienced by 57 autistic students (2.0%) with high-need funding and 447 autistic students (6.5%) without high-need funding. After adjustment for demographic characteristics, co-occurring conditions, and level of disability support need, autistic students with high-need funding had significantly lower odds of suspension than autistic students without high-need funding (adjusted odds ratio, 0.29; 95% CI, 0.21-0.40). Conclusions and Relevance: In this cohort study, the findings of disparities in suspension rates between autistic and nonautistic students underscore the challenges faced in providing inclusive education for all young people, regardless of disability status. This study found that high-need funding was associated with reduced suspension rates among autistic students, suggesting that if appropriate supports are afforded to autistic students, a more inclusive education can be provided.

Examining the sustainability of effects of early childhood obesity prevention interventions: Follow-up of the EPOCH individual participant data prospective meta-analysis.

BACKGROUND: Although early childhood obesity prevention has become an important issue internationally, little evidence exists regarding longer term effects (i.e., sustainability) of early interventions. OBJECTIVE: To determine whether intervention benefits at 2 years of age were sustained at 3.5 and 5 years. METHODS: Follow-up of the Early Prevention of Obesity in Children (EPOCH) individual participant data prospective meta-analysis of four randomized controlled trials including 2196 mother-child dyads at baseline. Interventions were home- or community-based, commenced within 6 months of birth, ended by 2 years of age, and comprised multiple sessions. Controls received standard care. BMI z-score (primary outcome), other anthropometric measures and weight-related behaviours were initially measured at 1.5-2 years and followed up at 3.5 and 5 years. RESULTS: Positive intervention effects on BMI z-scores at 1.5-2 years of age were not apparent by 3.5 years (-0.04 adjusted mean difference; 95% CI:-0.14, 0.06; p = 0.424), and 5 years (0.03; 95% CI: -0.08, 0.14; p = 0.60). While prolonged intervention benefits were detected for a few, but not the majority of, weight-related behaviours at 3.5 years, these effects diminished over time. CONCLUSION: This meta-analysis found that initial positive effects of childhood obesity interventions faded out after interventions ended, pointing toward the importance of a suite of interventions implemented at multiple stages across childhood.

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

AKT mutant allele-specific activation dictates pharmacologic sensitivities.

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.

Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer.

BACKGROUND: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. METHODS: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes. RESULTS: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n = 54), CHEK2 (n = 30), and ATM (n = 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P = 1.7e-04). CONCLUSIONS: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. IMPACT: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.

Anatomic position determines oncogenic specificity in melanoma.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers.

The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.