NEW YORK – Using a multiomic approach, a team from China has teased out molecular features found within and across metastatic hepatocellular carcinoma (HCC) tumors over time, uncovering diverse tumor clones showing early metastatic spread.
"HCC metastasis is traditionally viewed as the end-product of disease," Yunfan Sun, a liver surgery researcher with Fudan University's Liver Cancer Institute, explained in an email. "However, our data show a high degree of genetic divergence between primary HCCs and metastases, reflecting that metastatic precursors emerge early in evolutionary history."
As they reported in Cancer Cell on Thursday, co-first author Sun and his colleagues relied on exome sequencing and RNA sequencing to profile 461 formalin-fixed paraffin-embedded tumor regions from 182 individuals with metastatic HCC (mHCC) tumors of the lung, bone, brain, kidney, adrenal gland, lymph node, spleen, diaphragm, or peritoneum.
Based on genomic and transcriptomic profiles, which were analyzed in combination with digital spatial profiling (DSP), histopathology, T-cell receptor repertoire, and single-cell RNA-seq data on the metastatic tumors, the team characterized the genetic heterogeneity found in mHCC tumors.
"Despite progress in surveillance and treatment strategies that have improved overall survival rates, metastasis is still the major cause of patient mortality and remains largely incurable in HCC," Sun said, noting that "better understanding of metastasis is thus desperately needed to improve the prognosis of late-stage HCC patients."
In the process, the researchers flagged suspected driver mutations in the metastatic tumors, including somatic copy number alterations, while also highlighting primary tumor alterations that tend to be lacking in the HCC metastases, such as alterations affecting the Wnt signaling pathway.
"Consistent with previous studies in other cancer types, we do not discover recurrent metastasis-specific mutations," Sun explained. "However, increased global genome instability is evident in metastatic HCCs, suggesting somatic copy number events might play a critical role in enabling metastatic potential."
Using data from a subset of mHCC patients with multi-regional metastatic tumor samples, meanwhile, the investigators distinguished between metastatic seeding events marked by individual tumor subclones or seeding by multiple subclones and then linked polyclonal seeding to poorer patient outcomes.
The genomic divergence found between primary and metastatic tumors also pointed to early metastatic seeding at sites outside of the liver, meanwhile, hinting that there may be a previously unappreciated opportunity to stamp out micro-metastases in individuals being treated surgically with curative intent for localized HCC who might have occult cancer cell spread beyond the liver, Sun said.
He added that "neoadjuvant therapy in patients with resectable HCC might slow tumor progression and prevent further cancer cell dissemination," for example, while "postoperative adjuvant therapy might help eradicate minimal residual disease."
Beyond a new appreciation for the tumor alterations present in the extrahepatic HCC metastases, the investigators went on to explore the relationships between these tumor features, the immune system, and tumor microenvironment.
Although the mHCC tumors were often marked by high intratumor heterogeneity (ITH) that would be expected to produce neoantigen targets for the immune system, for example, their results revealed reduced T cell immune responses to high ITC, high neoantigen tumors — an effect that they attributed to altered antigen presentation capabilities.
"[W]e found evidence that tumor cells from neoantigen ITH-high metastases acquired genetic aberrations that disrupted antigen presentation after their metastatic seeding, which might lead to reduced immunogenicity," Sun explained.
Because past studies have described durable immune checkpoint blockade immunotherapy responses in advanced non-small cell lung cancer cases marked by low neoantigen ITH, Sun noted that the new findings may also offer neoantigen clues for predicting mHCC responses to checkpoint immunotherapy.
From these and other findings, Sun further suggested that "perioperative systemic therapies such as immune checkpoint blockade (ICB) could offer a survival benefit for resectable HCCs, which is of tremendous clinical significance in light of several phase II studies evaluating the role of perioperative immunotherapy."
On the other hand, Wnt-wild type mHCC tumors tended to correspond with a "reactive" or inflammatory tumor microenvironment containing cancer-associated fibroblasts, the authors explained, noting that "[r]eversing the fibro-inflammatory ecosystem might be an effective therapeutic strategy for preventing the onset of metastatic spreading."