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Pan-Cancer Genome Analyses Reveal Metastatic, Immune Escape Patterns

This article has been updated to correct that modest genomic differences were found in primary and metastatic tumors from pancreatic carcinoma, not prostate cancer.

NEW YORK – An international team led by investigators in the Netherlands has generated genome sequences for thousands of primary or metastatic tumors, providing a look at the genome features and alterations associated with advanced, treatment-resistant, or immune-dodging tumors from different cancer types.

"This is the first time a complete tumor genome-wide sequencing dataset has been generated for primary and metastatic tumors of this magnitude," corresponding author Edwin Cuppen, a human genetics researcher at the Center for Molecular Medicine and Oncode Institute at the University Medical Center Utrecht and scientific director of the Hartwig Medical Foundation in Amsterdam, said in an email.

"These data are public and available for research," he added, "providing a new global resource for further research into the biology and evolution of cancer, as well as the development of new therapies to combat the disease."

As they reported in Nature on Wednesday, the researchers used whole-genome sequencing done with a uniform sample processing approach, and the researchers initially analyzed more than 7,100 primary or metastatic tumors spanning 71 cancer types. The set included 1,914 primary and 3,451 metastatic tumors from 23 cancer types in 14 tissues that had sufficient data to compare primary and metastatic mutation landscape patterns.

"[O]ur dataset constitutes a valuable resource that can be leveraged to further study other aspects of tumor evolution, such as genomic differences across metastatic biopsy locations, dedicated analysis for cancer subtypes, [and] genetic immune escape alterations in primary and metastatic tumors, as well as for the development of machine learning tools to foster cancer diagnostics," the authors wrote.

In particular, the researchers saw diminished levels of intratumoral heterogeneity in the metastatic tumors overall, despite enhanced genome instability and a rise in structural variant levels. Even so, the specific patterns found in primary and metastatic tumors varied depending on the cancer type or subtype considered.

While the team's analyses pointed to relatively modest genomic differences in primary and metastatic tumors from pancreatic carcinoma and many other cancer types, for example, it highlighted dramatic changes in metastatic tumors from breast cancer, prostate cancer, thyroid cancer, renal cell carcinoma, and pancreatic neuroendocrine cancer types relative to the primary tumors profiled in these cancer types.

Notably, the latter set included cancer types with relatively robust treatment response and favorable outcomes at the primary tumor stage, the authors reported, suggesting that metastatic tumors that do eventually arise in a subset of patients with these cancers are prone to particularly pronounced genomic changes during disease progression.

Likewise, past treatment exposures appeared to influence the extent to which metastatic tumor genomes diverged from those in primary tumors, the researchers reported, noting that the metastatic tumors tended to contain known and suspected treatment resistance-related alterations not found in primary tumors.

"[T]he differences are highly dependent on the type of cancer studied, as well as the tumor's exposure to previous anti-tumor treatments," Cuppen explained, noting that "the pan-cancer nature of the current study demonstrates which processes and mechanisms are shared between tumor types and also quantifies their prevalence per tumor type."

In a related study published in Nature Genetics on Wednesday, members of the team analyzed whole-genome sequences for a set of 6,319 uniformly processed primary and metastatic tumor samples, focusing on genetic features that help the tumors dodge host immune system responses to cancer.

When they looked at half a dozen immune escape pathways in this sequence collection, the investigators uncovered genetic immune escape features in roughly one-quarter of the tumors profiled.

Although such features turned up to a comparable extent in the primary and metastatic tumors in general, they reported, the frequency of genetic immune escape and the specific mechanisms at play varied by cancer type and in relation to the mutational burden found within a given tumor.

"We found that prevalence of genetic immune escape is highly variable between tumor types and that in certain tumor types only a single mechanism is present, while in others, various processes were affected," Cuppen said. "Furthermore, we show that there are not [many] differences between primary and metastatic tumors, indicating that immune evasion is a characteristic that is acquired relatively early in tumor development."

That analysis also revealed selection for specific immune escape features as tumors evolved, including selection for loss-of-heterozygosity (LOH) events affecting the human leukocyte antigen HLA-I locus, which was particularly common for tumors with high or medium levels of tumor mutational burden (TMB). In contrast, the team identified distinct methods for circumventing the immune system in a subset of tumors marked by hypermethylation.

"Although focal LOH of HLA-I was the most frequent mechanism in mid and high TMB tumors, the loss of certain HLA-I alleles was apparently not sufficient to cope with the neoepitope load of (ultra)hypermutated tumors, where a nontargeted [genetic immune escape] mechanism, such as antigen presentation abrogation, is probably needed."