Biologic factors linked to recurrence of BRCA1/BRCA2-mutated breast, ovarian cancers
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A study conducted at University of Pennsylvania’s Abramson Cancer Center has revealed possible drivers of recurrence in breast and ovarian tumors with BRCA1/BRCA2 mutations.
The study, published in Nature Communications, evaluated 67 sets of primary and recurrent breast and ovarian tumors from carriers of BRCA1/BRCA2 mutations. For each matched set, they compared the DNA mutations, patterns of gene activity and other tumor cell features in the primary tumor and identified differences between the primary and recurrent tumor.
“We specifically looked at matched primary and recurrent tumors, because if you really want to understand the determinants of recurrence in a tumor type, you need to have both the primary and the recurrent tumor,” senior study author Katherine L. Nathanson, MD, Pearl Basser professor for BRCA-related research at Penn’s Perelman School of Medicine, deputy director of Abramson Cancer Center, and director of genetics at Basser Center for BRCA, told Healio. “If you focus on primary and recurrent tumors that are matched, you can have a much more detailed understanding of tumor development.”
Nathanson spoke with Healio about study results and what they might reveal about the mechanisms of cancer recurrence.
Healio: What did you find when you studied these matched sets of tumors?
Nathanson: We had three primary findings in our paper. We found that poly(ADP-ribose) polymerase-1 (PARP-1) was a target of amplification. This finding is important because PARP-1 is a target of olaparib [Lynparza; AstraZeneca, Merck] and all PARP inhibitors. We found it was initially more amplified in our recurrent breast cancer tumors, but when we reanalyzed both our data and the Cancer Genome Atlas data, we found PARP-1 is amplified quite frequently across both breast and ovarian cancers, independent of BRCA1 and BRCA2 statuses. Additionally, we discovered it is overexpressed in RNA studies, independent of the level of amplification. PARP overexpression has not been looked at as a biomarker for PARP response. We found it was consistently overexpressed and suggest it be looked at on the protein level as a biomarker.
When we looked at the determinants of recurrence, we discovered presence of allele-specific loss of heterozygosity of BRCA1 and BRCA2 as tumors develop is not as static as we might think. A group of primary tumors had no allele-specific loss of heterozygosity (LOH) in the primary, and then lost heterozygosity in the recurrence, which looked to be a factor of tumor progression.
In contrast, we saw some tumors with allele-specific LOH of the primary, with recurrent tumors without allele-specific LOH. There are probably several explanations for that. One is an outgrowth of a subclone that did not have LOH. We could see, for example that there was a p53 mutation in one tumor that was at 1% frequency in the primary and at 30% frequency in the recurrence, supporting growth of a subclone. There has been some prior literature that suggests you can get transient differences in LOH, particularly as a marker of resistance to platinum chemotherapy.
Our third finding was from RNA data — which hasn’t gotten a lot of attention — specifically looking at isoform switching, which involves going between different splice variants. We found two isoforms of BRCA2. The one that was less sensitive to degradation was much more frequently found in the recurrences in general, and particularly in BRCA1-mutated tumors. We also found a significant association between the presence of a BRCA2 isoform less sensitive to degradation in any tumor and decreased overall survival.
We also identified known findings, such as that TP53 mutations are by far the most common other mutations in BRCA1 and BRCA2 tumors. We also found a subset of BRCA1- and BRCA2-associated tumors that do not undergo allele-specific LOH for BRCA1/2.
Healio: What do you have planned next in your research on this?
Nathanson: Our lab has researched issues related to BRCA1 and BRCA2 mutations for a long time. In looking at the tumors of BRCA1 and BRCA2, there are a number of areas we’re particularly interested in continuing our studies. One is linking these molecular findings to how these tumor characteristics might be associated with differences in the immune microenvironment. We’re also very interested in trying to look at a single cell and understand why some cells have LOH and some do not, and how can we evaluate that on the single-cell level. This question is one among many that we are investigating further.
For more information:
Katherine L. Nathanson, MD, can be reached at 3400 Civic Center Blvd., South Pavilion, 1st Floor, Philadelphia, PA 19104; email: knathans@upenn.edu.
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