Fig. 2: FAT1 loss of function is enriched in the TRACERx 421 cohort and leads to an elevated mitotic error rate and WGD. | Nature Cell Biology

Fig. 2: FAT1 loss of function is enriched in the TRACERx 421 cohort and leads to an elevated mitotic error rate and WGD.

From: TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling

Fig. 2

a, Top, schematic of dN/dS ratio analysis. Bottom, results of dN/dS ratio analysis in the TRACERx 421 cohort, demonstrating that FAT1 truncation mutations are selected early in LUSC tumour evolution. The data points represent estimated dN/dS ratios and the error bars represent 95% confidence intervals calculated using the genesetdnds function from the R package dNdScv. The TRACERx 421 cohort comprised 233 males and 188 females (421 patients total), corresponding to a 55:45 male:female ratio. 93% of the cohort was from a White ethnic background and the mean age of the patients was 69 years, ranging between 34 and 92 years. Written informed consent was obtained. None of the patients was compensated for their involvement in the study. b, Genomic identification of significant targets In cancer (GISTIC) analysis of LUAD (141 patients) and LUSC tumours (80 patients) in TRACERx with clonal WGD only, demonstrating that SCNA loss at the FAT1 genomic locus (4q35.2; red text and highlighted) is positively selected in tumours with clonal WGD only. SCNA loci overlapping with common or rare chromosome fragile sites72,73 are annotated (in blue for common fragile sites and in green for rare fragile sites). c, MSAI analysis illustrating that the genomic region of chromosome 4 that harbours the FAT1 gene (arrows) is frequently lost in LUSC. Statistical significance was determined by Fisher’s exact test. In the schematic at the top, paternal and maternal chromosomes are indicated in blue and red, respectively. d, Top, schematic illustrating the location of the FAT1 gene on chromosome 4, together with other 4q35.2 genes within the frequently lost 4q35.2 genomic region. Bottom, selection pressures against losing genes. The data are from the Genome Aggregation Database (gnomAD) and demonstrate high selective pressure against deletion of the FAT1 genomic locus within 4q35.2. exp, expected; LOF, loss of function; obs, observed.

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