Bryant, A. | Search bioRxiv

bioRxiv2018

Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

cancer biology↗

bioRxiv2018

A transdiagnostic study of children with problems of attention, learning and memory (CALM)

BackgroundA substantial proportion of the school-age population experience cognitive-related learning difficulties. Not all children who struggle at school receive a diagnosis, yet their problems are sufficient to warrant additional support. Understanding the causes of learning difficulties is the key to developing effective prevention and intervention strategies for struggling learners. The aim of this project is to apply a transdiagnostic approach to children with cognitive developmental difficulties related to learning to discover the underpinning mechanisms of learning problems.\n\nMethods / DesignA cohort of 1000 children aged 5 to 18 years is being recruited. The sample consists of 800 children with problems in attention, learning and / memory, as identified by a health or educational professional, and 200 typically-developing children recruited from the same schools as those with difficulties. All children are completing assessments of cognition, including tests of phonological processing, short-term and working memory, attention, executive function and processing speed. Their parents/ carers are completing questionnaires about the childs family history, communication skills, mental health and behaviour. Children are invited for an optional MRI brain scan and are asked to provide an optional DNA sample (saliva).\n\nHypothesis-free data-driven methods will be used to identify the cognitive, behavioural and neural dimensions of learning difficulties. Machine-learning approaches will be used to map the multi-dimensional space of the cognitive, neural and behavioural measures to identify clusters of children with shared profiles. Finally, group comparisons will be used to test theories of development and disorder.\n\nDiscussionOur multi-systems approach to identifying the causes of learning difficulties in a heterogeneous sample of struggling learners provides a novel way to enhance our understanding of the common and complex needs of the majority of children who struggle at school. Our broad recruitment criteria targeting all children with cognitive learning problems, irrespective of diagnoses and comorbidities, are novel and make our sample unique. Our dataset will also provide a valuable resource of genetic, imaging and cognitive developmental data for the scientific community.

neuroscience↗