Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis. Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. These shared transcriptomic alterations could help explain epidemiological observations suggesting direct and inverse comorbid associations between ASD and particular cancer types.

CTCs)) and tumour biopsy samples. Results: The median age of pts was 56 (range 32-75). 48% (33/68) were colon tumours, 34% (23/68) rectal, 9% (6/68) rectosigmoid and 7% (5/68) small bowel. Pts had failed an average of 3 lines (range 1-5) of treatment prior to recruitment. 74% (50/68) of patients had both sufficient tumour DNA in their plasma, and archival biopsies for analysis. Sequencing of ctDNA detected all mutations reported in tumour in 76% (38/ 50) of pts. ctDNA analysis picked up additional mutations in 30% (15/50) of pts. The interval between collection of archival biopsies and blood tests (p ¼ 0.300) did not affect detection of new mutations. 31% (6/19) of pts treated with anti-EGFR therapy developed recognised resistance mutations (KRAS and EGFR) in ctDNA on serial analysis. The most commonly detected mutations were TP53 (60%), KRAS (51%), PIK3CA (15%) and PTEN (3%). Other mutated genes included CTNNB1, BRAF, FGFR3 and ERRB2. Pre-clinical models (organoids and patient-derived xenografts (PDX)) were attempted from blood (CTCs) and/or tumour tissue in 29% (20/68) of pts. CTC organoid cultures were optimised and successful in 1/17 pts. Conclusions: ctDNA may be used for routine molecular characterisation of metastatic SBC/CRC and results can be analysed to track the development of resistance.

Methods: OE19 and NCIN87, HER2þ GC cell lines were treated with increasing doses of Lapatinib (L) and Trastuzumab (T) to obtain resistant clones. These were isolated and characterized by performing mutational analysis and protein expression by Western blot (WB). Genome expression profile was done by ClariomS microarray. Inhibition of the altered pathways was evaluated using a panel of selected drugs. siRNAs were performed to characterise the role of the inhibition of selected proteins. An in vivo experiment was conducted to corroborate results. A retrospective cohort of HER2 amplified patients treated with T was analysed. An immunohistochemistry (IHC) analysis to evaluate the altered pathway detected in preclinical models was conducted. Results: L and T resistant clones were obtained. In resistant cells, protein expression underlined the activation of PI3K pathway and of its downstream effector RPS6 protein. Analysing microarray, it was possible to identify, the activation of a large number of genes regulated by NFR2. Its expression was confirmed by WB; NRF2 nuclear activation was detected by nuclear fractionating WB and immunofluorescence. A panel of target agents was used to evaluate NRF2 changes. It was possible to observe the its expression strongly decrease by using PI3K pathway inhibitors, suggesting a relation between this pathway and NRF2. To better clarify this phenomenon, siRNA of RPS6, that was detected to be activated in resistant cells, was performed and it was possible to observe a strong decrease of NRF2 expression and sensitivity to antiHER2 drugs was restored. IHC of both RPS6 and NRF2 were performed suggesting that the activation of both RPS6 and NRF2 related with less clinical benefit of T. Conclusions: RPS6 through the activation of NRF2 should be considered a new mechanism responsible for antiHER2 drugs resistance in GC. Further investigations are needed.