Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes
Curator: Aviva Lev-Ari, PhD, RN
This Open Access Online Scientific Journal represents a repository of curated scientific literature on the following types of cancer of relevance to the subject matter of this article. See below the FRONTIER of Research on:
Breast Cancer
http://pharmaceuticalintelligence.com/?s=Breast+Cancer
Ovarian Cancer
http://pharmaceuticalintelligence.com/?s=Ovarian+Cancer
Genomics of Endometriosis
http://pharmaceuticalintelligence.com/?s=Endometriosis+
Reproductive Genomics
http://pharmaceuticalintelligence.com/?s=Reproductive+Genomics
Genomic Endocrinology
http://pharmaceuticalintelligence.com/?s=Endocrinology+Genomic
Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes – New Findings
CONCLUSIONS
- the team saw an apparent jump in PD-1 representation in the lymphocytes that were infiltrating neighboring tumors in the BRCA1/2-mutated tumors relative to the other ovarian cancers, though staining for the immune checkpoint contributors within tumors themselves appeared similar regardless of the subtype considered.
- Strickland and his colleagues reasoned that such a feature may partly explain the relatively high progression-free survival and overall survival rates reported in BRCA1/2-mutated ovarian cancers, though they are continuing to study the relationship between BRCA mutations and tumor features.
- Memorial Sloan Kettering medical oncologist Alexandra Snyder Charen discussed potential implications of the endometrial and ovarian cancer studies, noting that distinct mutation signatures in different tumor types could also affect immune response.
- While she expressed enthusiasm about potential treatment clues provided by more-or-less mutated endometrial and ovarian cancers, Snyder Charen noted that additional research is needed on additional forms of the disease, since the work described was done using primary tumors.
Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors
Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
TCGA Analysis Uncovers Four Molecular Subtypes for Endometrial Cancer
For tumors from the high-risk serous subtype, meanwhile, they saw genetic and genomic features that resemble those found in serous ovarian cancer and basal-like breast cancer, albeit with more frequent mutations to genes such as PIK3CA, FBXW7, PPP2R1A, and ARID1A.
These and other molecular features identified in the current study could have prognostic and treatment implications, they noted. For instance, survival patterns in the POLE subtype seem to be favorable, despite the rampant mutations present in the genomes of those tumors.
In contrast, individuals with serous or serous-like tumors appear to do much worse, Levine noted.
That, in turn, suggests that there could be a benefit to offering more aggressive treatment to individuals with endometrioid cases falling in the new serous-like category, which is characterized by a higher-than-usual burden of copy number changes coupled with frequent mutations in the TP53 gene, a common cancer culprit.
“Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiation,” Levine and his co-authors wrote, “and formally test such hypotheses in prospective clinical trials.”
For their part, researchers involved in the current study recently completed the accrual process for a clinical trial that will involve a little more than 300 endometrial cancer patients being treated with various chemotherapy regimens.
By prospectively collecting and tumors and determining their molecular subtypes, Levine said, it should be possible to track outcomes in relation to the four subtypes identified in the current study and, eventually, to get a better sense of treatment response and survival patterns in each group.
Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes
researchers from Brigham and Women’s Hospital, Harvard Medical School, and the Dana-Farber Cancer Institute characterized tumor-infiltrating immune cell activity and immune checkpoint contributor expression in dozens of archival endometrial tumors samples from mutation-heavy polymerase epsilon (POLE) mutations and microsatellite instability subtypes, comparing them with patterns in more mutation-light microsatellite stable tumors.
The results suggest endometrial cancers from subtypes prone to more widespread mutation also trigger stronger immune responses that might be further enhanced by drugs that inhibit cancer cells’ immune checkpoints, explained Brooke Howitt, a pathologist at the Brigham and Women’s Hospital, who presented the research at ASCO.
Howitt and her colleagues used immunohistochemistry to profile tumor infiltrating lymphocyte and expression of the immune checkpoint players PD-1 and PD-L1 in four POLE-mutated endometrial cancers, 28 endometrial cancers with microsatellite instability, and 32 microsatellite stable endometrial cancers.
Indeed, their results pointed to more pronounced tumor infiltration by CD3+ , CD4+, and CD8+ lymphocytes in the group of POLE-mutated and microsatellite unstable tumors than in the microsatellite stable subtype, consistent with T-cell activity against the mutation-rich tumors.
When they compared the more mutated endometrial cancer subtypes to the microsatellite stable group, the researchers saw signs of enhanced PD-L1 and PD-1 expression in both infiltrating lymphocytes and in the tumors themselves, hinting that the oft-mutated subtypes may respond to immune-targeting PD-1 inhibitor drugs.
Dana-Farber Cancer Institute researcher Kyle Strickland provided evidence for a similar pattern of bolstered immune activity against extensively mutated tumors.
For their part, though, Strickland and his team focused on BRCA1- and/or BRCA2-mutated, high-grade serous ovarian cancers, using immunohistochemistry to see if the high mutational load found in tumors with hampered BRCA-mediated DNA repair activity might also be a flag for the immune system.
There, researchers compared tumor infiltrating lymphocyte patterns in 37 BRCA1/2-mutated tumor samples and in samples from 16 tumors lacking germline or somatic mutations in BRCA1, BRCA2, or related mutations or expression changes — features verified by high-throughput sequencing.
Results from that comparison suggested that all of the ovarian cancers had comparable levels of certain tumor infiltrating lymphocytes, such as the CD3+ or CD20+ lymphocytes.
But compared with the “homologous recombination intact” tumors, the BRCA1/2-mutated ovarian cancers appeared to be marked by higher CD8+ tumor infiltrating lymphocytes and lower CD4+ tumor infiltrating lymphocytes, Strickland explained.
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