Abstract
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.
Highlights
Primary liver cancer (PLC), mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second most deadly and fourth most common cancer worldwide [1]
whole-exome sequencing (WES) was performed on synchronous multifocal PLC (2 HCC tumors, HCC-A and HCC-B; 1 ICC tumor; Figure 1A and Supplementary Figure 1) and two intrahepatic recurrent tumors (IM1 and IM2; Figure 1A and Supplementary Figure 2) of a patient for genetic comparisons (Supplementary Table 1 )
The heatmap of variant allele frequencies (VAF) of the single nucleotide variants (SNVs) revealed 3 clear blocks corresponding to SNVs only discovered in HCC-A, HCC-B and ICC, respectively (Figure 2B)
Summary
Primary liver cancer (PLC), mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second most deadly and fourth most common cancer worldwide [1]. A recent national survey in Japan showed that half of the PLCs, especially HCC, were multiple lesions [4] Chronic liver damage, such as that caused by chronic hepatitis and www.impactjournals.com/oncotarget liver cirrhosis, is closely associated with the occurrence of both HCC and ICC [5]. The molecular pathogenesis and genetic variability of multifocal PLC remains largely unknown, bringing a great challenge to effective molecularly targeted therapies in those patients. In this regard, next-generation sequencing was advocated to determine the genetic heterogeneity in different tumor sites or in multiple tumors to identify any driver event that may have functional, prognostic, and therapeutic implications [11]
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