NEW YORK (GenomeWeb) – A copy number amplification of a stretch of chromosome 1 could serve as a marker for breast cancer recurrence risk as well as a therapeutic target, according to an international team of researchers.
As they reported in Nature Medicine yesterday, the scientists, led by the Genome Institute of Singapore's Qiang Yu and colleagues, found that tumor-initiating cells often harbor an amplification at chromosome 1q21.3. They developed a blood-based assay to detect the amplification, which they said could serve as a biomarker for disease relapse and treatment response. The researchers also uncovered a functional link between genes encoded at chromosome 1q21.3 and IL-1 receptor-associated kinase 1 (IRAK1) that may drive tumor growth, and suggested a potential therapeutic approach.
"We propose that, for early-stage patients, detection of 1q21.3 amplification could identify a subgroup of women with particularly aggressive tumors; this has important implications for prognostication as well as treatment recommendations," Yu and colleagues wrote.
The researchers compared the RNA sequencing profiles of tumor-initiating cells and matched bulk tumor cells obtained from a dozen cancer patients. From this, they uncovered some 1,400 genes whose expression was higher in the tumor-initiating cells. By examining whether any of these genes were associated with copy number alterations, the researchers homed in on two regions, but only one region of copy number changes — at 1q21.3 — was associated with breast cancer progression.
After validating this finding, the researchers developed a droplet digital PCR assay to detect the 1q21.3 amplification in blood samples. They reported that the ddPCR assay could detect the amplification with a sensitivity of 93.3 percent and a specificity of 97.5 percent from cell-free DNA in plasma samples.
The researchers also explored whether the 1q21.3 amplification might be able to catch disease recurrence. They analyzed primary tumor samples from both patients who relapsed and those who did not. Two of the 28 primary tumor samples from patients who didn't relapse had the amplification, while 12 tumor samples from 34 patients who went on to relapse had it.
They also examined if the amplification was associated with clinical outcomes. Using the ddPCR assay as a liquid biopsy test, they analyzed a cohort of 80 patients newly diagnosed with stage 1 or stage 2 tumors. Four patients had the amplification, and all four relapsed within five years, the researchers reported. Likewise, in a cohort of stage 2 and stage 3 breast cancer patients, all eight patients who harbored the amplification relapsed.
At the same, the researchers found that their assay could be used to monitor chemotherapy response. In a retrospective study of a cohort of patients given gemcitabine and carboplatin, they found that patients with a 1q21.3 amplifications at baseline became negative for it about a week into treatment, but then the amplification reappeared and most patients relapsed. The blood-based assay, though, caught that relapse an average of 2.2 months earlier than a conventional radiological scan did, the researchers reported.
The 1q21.3 region of chromosome 1 harbors some 17 members of the S100A gene family, which activates IRAK-NF-kappaB signaling and is involved in breast cancer metastasis. In a series of cell line and other studies, they found that S100A7, S100A8, and S100A9 expression was closely correlated with 1q21.3 amplification and that S100A7, S100A8, and S100A9 and IRAK1 together form a regulatory circuit that drives growth.
However, the researchers noted that this circuit is targetable with a drug. Pacritinib, a JAK2 inhibitor, is also thought to be an IRAK1 inhibitor, and when the researchers treated cells overexpressing IRAK1 with pacritinib, growth was disrupted. Additionally, pacritinib treatment was more effective in cells and mice with 1q21.3 amplifications than in those without. In mice, they noted that the combination of pacritinib and paclitaxel led to tumor regression that lasted up to two months.
"Our study uncovers the 1q21.3-directed S100A7/8/9–IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer," the researchers wrote.