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Multifocal tumors developed either as independent tumors or as intrahepatic metastases, are very common in primary liver cancer. However, their molecular pathogenesis remains elusive. Herein, a patient with synchronous two hepatocellular carcinoma (HCC, designated as HCC-A and HCC-B) and one intrahepatic cholangiocarcinoma (ICC), as well as two postoperative recurrent tumors, was enrolled. Multiregional whole-exome sequencing was applied to these tumors to delineate the clonality and heterogeneity. The three primary tumors showed almost no overlaps in mutations and copy number variations. Within each tumor, multiregional sequencing data showed varied intratumoral heterogeneity (21.6% in HCC-A, 20.4% in HCC-B, 53.2% in ICC). The mutational profile of two recurrent tumors showed obvious similarity with HCC-A (86.7% and 86.6% respectively), rather than others, indicating that they originated from HCC-A. The evolutionary history of the two recurrent tumors indicated that intrahepatic micro-metastasis could be an early event during HCC progression. Notably, FAT4 was the only gene mutated in two primary HCCs and the recurrences. Mutation prevalence screen and functional experiments showed that FAT4, harboring somatic coding mutations in 26.7% of HCC, could potently inhibit growth and invasion of HCC cells. In HCC patients, both FAT4 expression and FAT4 mutational status significantly correlated with patient prognosis. Together, our findings suggest that spatial and temporal dissection of genomic alterations during the progression of multifocal liver cancer may help to elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC.

Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity