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Pan-Cancer Analysis Links Whole-Genome Doubling to Poorer Advanced Cancer Outcomes

NEW YORK (GenomeWeb) – A Memorial Sloan Kettering Cancer Center-led team has started documenting the role that whole-genome doubling (WGD) may play in the dynamics of different cancer types and subtypes.

The researchers prospectively generated targeted sequence data for nearly 10,000 advanced cancer cases, identifying WGD in almost one-third of the tumors. Their follow-up analyses suggested these WGD events often occurred relatively early on in the cancer development process, arising more frequently in tumors from certain lineages or cancer subtypes. 

Along with investigations into the molecular features that tend to accompany WGDs, the team delved into the clinical outcomes for patients with WGD tumors, uncovering evidence for poorer outcomes and increased morbidity in the cases involving WGDs across cancer types. The results appeared online today in Nature Genetics.

"The ability of WGD to identify poor prognosis primary tumors, as in the case of the pancreatic cancers profiled here, could inform the design of new adjuvant trials in specific populations of high-risk patients," corresponding author Barry Taylor, an oncology, epidemiology, and biostatistics researcher at MSKCC, and his colleagues wrote, noting that "concurrent sequencing of matched normal specimens from cancer patients is essential for its robust detection."

The team did targeted sequencing on matched tumor and normal blood samples from 9,692 consecutive advanced cancer cases, representing 55 tumor types, using the MSK-IMPACT sequencing platform. More than 28 percent of the tumors showed signs of WGD, the group reported, including nearly 60 percent of germ cell tumors, but just a fraction of non-Hodgkin lymphomas and gastrointestinal neuroendocrine tumors.

The prevalence of WGD appeared to vary by cancer subtype and with distinct molecular features as well, the researchers explained, prompting a closer investigation of related genomic alterations, tumor trajectory, and patient outcomes.

"Upon determining the likely presence or absence of WGD in the cancer genomes of 9,692 prospectively sequenced patients, we sought to systematically assess its evolutionary impact, genomic associations, and prognostic significance in both common and rare cancer, and to evaluate whether the availability of such information could ultimately impact clinical management," they wrote.

Although WGD was far more common in tumors containing TP53 mutations, for example, more than one-fifth of tumors with wild-type TP53 — particularly those containing CCND1 amplifications or displaying E2F-mediated G1 arrest — also underwent WGD. These duplications appeared to follow early driver mutation events, the team reported, and WGD closely corresponded with tumor proliferative indexes gleaned from RNA sequence data for more than 10,500 tumor samples profiled for the Cancer Genome Atlas project.

When the researchers folded in survival data, they found that WGD was consistently associated with shorter overall survival times in their pan-cancer analysis and in specific cancer types including pancreatic cancers and KRAS-mutant colorectal cancers.

"[O]ur analysis of WGD was performed in prospectively characterized cancer patients using clinical sequencing data, the results of which could be practice-changing if evidence-based guidelines can be established for the use of this information to inform clinical decision-making," Taylor and co-authors concluded.

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