X

Quality Statement

Pacific Biosciences is committed to providing high-quality products that meet customer expectations and comply with regulations. We will achieve these goals by adhering to and maintaining an effective quality-management system designed to ensure product quality, performance, and safety.

X

Image Use Agreement

By downloading, copying, or making any use of the images located on this website (“Site”) you acknowledge that you have read and understand, and agree to, the terms of this Image Usage Agreement, as well as the terms provided on the Legal Notices webpage, which together govern your use of the images as provided below. If you do not agree to such terms, do not download, copy or use the images in any way, unless you have written permission signed by an authorized Pacific Biosciences representative.

Subject to the terms of this Agreement and the terms provided on the Legal Notices webpage (to the extent they do not conflict with the terms of this Agreement), you may use the images on the Site solely for (a) editorial use by press and/or industry analysts, (b) in connection with a normal, peer-reviewed, scientific publication, book or presentation, or the like. You may not alter or modify any image, in whole or in part, for any reason. You may not use any image in a manner that misrepresents the associated Pacific Biosciences product, service or technology or any associated characteristics, data, or properties thereof. You also may not use any image in a manner that denotes some representation or warranty (express, implied or statutory) from Pacific Biosciences of the product, service or technology. The rights granted by this Agreement are personal to you and are not transferable by you to another party.

You, and not Pacific Biosciences, are responsible for your use of the images. You acknowledge and agree that any misuse of the images or breach of this Agreement will cause Pacific Biosciences irreparable harm. Pacific Biosciences is either an owner or licensee of the image, and not an agent for the owner. You agree to give Pacific Biosciences a credit line as follows: "Courtesy of Pacific Biosciences of California, Inc., Menlo Park, CA, USA" and also include any other credits or acknowledgments noted by Pacific Biosciences. You must include any copyright notice originally included with the images on all copies.

IMAGES ARE PROVIDED BY Pacific Biosciences ON AN "AS-IS" BASIS. Pacific Biosciences DISCLAIMS ALL REPRESENTATIONS AND WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, INCLUDING, BUT NOT LIMITED TO, NON-INFRINGEMENT, OWNERSHIP, MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. IN NO EVENT SHALL Pacific Biosciences BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, PUNITIVE, OR CONSEQUENTIAL DAMAGES OF ANY KIND WHATSOEVER WITH RESPECT TO THE IMAGES.

You agree that Pacific Biosciences may terminate your access to and use of the images located on the PacificBiosciences.com website at any time and without prior notice, if it considers you to have violated any of the terms of this Image Use Agreement. You agree to indemnify, defend and hold harmless Pacific Biosciences, its officers, directors, employees, agents, licensors, suppliers and any third party information providers to the Site from and against all losses, expenses, damages and costs, including reasonable attorneys' fees, resulting from any violation by you of the terms of this Image Use Agreement or Pacific Biosciences' termination of your access to or use of the Site. Termination will not affect Pacific Biosciences' rights or your obligations which accrued before the termination.

I have read and understand, and agree to, the Image Usage Agreement.

I disagree and would like to return to the Pacific Biosciences home page.

Pacific Biosciences
Contact:

Double Mutations in Oncogene May Improve Patient Response to Targeted Therapy

Friday, November 8, 2019

The PIK3CA oncogene has been the target of intense research scrutiny for decades. Remarkably, though, a new paper in Science today reports completely novel findings about compound mutations that are associated with patients who respond extremely well to targeted therapies. While more studies are needed, this work has important implications for delivering treatment to patients with breast cancer and other common cancers.

Neil Vasan

“Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors” comes from lead author Neil Vasan, senior authors Maurizio Scaltriti and José Baselga, and collaborators at Memorial Sloan Kettering Cancer Center, the Icahn School of Medicine at Mount Sinai, one pharma company, and other institutions. The project emerged from follow-up studies of a breast cancer patient previously identified as a super-responder to the targeted PI3Kα inhibitor alpelisib. It turned out the patient had double PIK3CA mutations, so scientists embarked on an effort to find out whether that mattered for response to treatment — and what they learned could change how oncologists approach therapy selection.

As it turns out, multiple PIK3CA mutations are far more common than expected; the vast majority are double mutations. Researchers detected them across a wide variety of cohorts in 12% to 15% of breast cancers and other types of cancer. Previously, that number was believed to be less than 1%.

According to the authors, that discrepancy can be attributed to the approaches traditionally used to analyze PIK3CA mutations in cancer genomes. “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. 

For this project, scientists deployed SMRT Sequencing to analyze the full PIK3CA gene, which not only gave them more complete information, but also allowed them to phase mutations and determine when the double mutations occurred in the same allele. “Establishing their allelic configuration is important because cis mutations would result in a single protein with two mutations, whereas trans mutations would result in two proteins with separate individual mutations, and these could have different functional consequences,” the team notes. 

But proving the mutations occurred in cis was no easy task. “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,” the team writes. “Our findings provide a rationale for testing whether patients with multiple–PIK3CA-mutant tumors are markedly sensitive to PI3Kα inhibitors.”

We caught up with Vasan shortly before this publication was released and asked him about the implications of these findings. “This gene has been so well studied for decades, it’s humbling that we found something new,” he told us. “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.”

Subscribe for blog updates:

Archives