TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
Creators: name: Lu, Wei-Ting
name: Zalmas, Lykourgos-Panagiotis
name: Bailey, Chris
name: Black, James RM
name: Martinez-Ruiz, Carlos
name: Pich, Oriol
name: Gimeno-Valiente, Francisco
name: Usaite, Ieva
name: Magness, Alastair
name: Thol, Kerstin
name: Webber, Thomas A
name: Jiang, Ming
name: Saunders, Rebecca E
name: Liu, Yun-Hsin
name: Biswas, Dhruva
name: Ige, Esther O
name: Aerne, Birgit
name: Grönroos, Eva
name: Venkatesan, Subramanian
name: Stavrou, Georgia
name: Karasaki, Takahiro
name: Al Bakir, Maise
name: Renshaw, Matthew
name: Xu, Hang
name: Schneider-Luftman, Deborah
name: Sharma, Natasha
name: Tovini, Laura
name: Consortium, TRACERx
name: Jamal-Hanjani, Mariam
name: McClelland, Sarah E
name: Litchfield, Kevin
name: Birkbak, Nicolai J
name: Howell, Michael
name: Tapon, Nicolas
name: Fugger, Kasper
name: McGranahan, Nicholas
name: Bartek, Jiri
name: Kanu, Nnennaya
name: Swanton, Charles
Publisher: name: The Francis Crick Institute
Year: 2025
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Chemical Biology & High Throughput
subject: Chemical Biology &amp; High Throughput
classificationCode: Ecology,Evolution & Ethology
subject: Ecology,Evolution &amp; Ethology
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms
classificationCode: Imaging
subject: Imaging
classificationCode: Cell Cycle & Chromosomes
subject: Cell Cycle &amp; Chromosomes

description: Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.