Multiple Cis Mutations Of PIK3CA Frequent In Cancer And Associated With Treatment Response

Pixabay License | Source: Arek Socha , no changes made.
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A new paper in Science magazine reports that double mutations of PIK3CA on the same allele (cis) are more common than previously thought with 12-15% of breast cancers and other tumor types harboring these cis mutations. Sequencing in cis was made possible by Pacific Biosciences (PacBio) technology. Importantly patients with these cis mutations responded extremely well to PIK3CA targeted therapies with implications for clinical practice.

Founded in 2004, headquartered in Menlo Park, California, PacBio develops comprehensive solutions for scientists that propel the field of genomics, improve science and research, and create positive impact globally. They provide sophisticated genomic analysis systems that deliver invaluable insights for scientists who strive to resolve complex genetic challenges.

The study was led by Neil Vasan, with senior authors Maurizio Scaltriti and José Baselga. The project emerged from follow-up studies of a breast cancer patient identified as a super-responder to the targeted PI3Kα inhibitor alpelisib. That research revealed double PIK3CA mutations, so the scientists embarked on a larger effort to find out whether that had significance for treatment response. What they learned could change the algorithms oncologists use for therapy selection in breast and other cancers.

The new study shows that multiple PIK3CA mutations, the vast majority of which are double mutations, are more common than expected. Researchers detected them across a wide variety of cohorts in 12% to 15% of breast cancers and other types of cancer. Previously, less than 1% of PIK3CA genes were thought to harbour double, or more, mutations.

“The common practice of sequencing only certain single-nucleotide variants or some but not all exons across a gene likely underestimates the frequency of multiple mutations in PIK3CA mutant cancers.” – Vasan et al. write.

“To study the allelic configuration of double mutations, we faced several technical hurdles based on our observation that the most frequent double PIK3CA mutants are located far apart in genomic DNA.” This meant that short-read and even Sanger sequencing could not span the distance.

It also meant that analyzing degraded DNA from FFPE samples would not support the kind of full-length sequence that was required. Researchers went back to patients and collected new samples that were frozen prior to sequencing. With those samples and long PacBio reads, scientists were able to distinguish patients with cis versus trans mutations.

“The overall consequence of these cis mutations is a phenotype of enhanced oncogenicity and greater sensitivity to PI3Ka inhibitors.” … “Our findings provide a rationale for testing whether patients with multiple–PIK3CA-mutant tumors are markedly sensitive to PI3Kα inhibitors.” – Vasan et al. write.

“This gene has been so well studied for decades, it’s humbling that we found something new.” … “In the cancer sequencing field, I think that we’ve hit a plateau in terms of single nucleotide variation. From a discovery point of view, we need to focus on higher-order interactions such as these double mutations.” – Neil Vasan, MD, PhD, lead author, Medical Oncologist, Memorial Sloan Kettering Cancer Center

Sources

  1. https://www.pacb.com/blog/double-mutations-in-oncogene/
  2. https://www.linkedin.com/company/pacific-biosciences/about/