Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

Abstract

Background: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. Methods: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census—CGC, the Candidate Cancer Gene Database—CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. Results: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67–83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20–35% TNBC (Y vs. E); DNA repair genes were mutated in 19–33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. Conclusion: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.

Whole exome analysis to select targeted therapies for patients with metastatic breast or advanced gynecological cancer: a feasibility study

“…From a clinical point of view [11,17,18] the most relevant GAs were: ESR1 (mutation, n = 1; as already described), RB1 (mutation, n = 2), CCNE1 (CNG, n = 5), FGFR1 (CNG, n = 5) and PIK3CA (mutation, n = 6; as stated before). Other GAs of clinical interest due to possible ineffectiveness [11,[19][20][21][22] detected in our collective are: NF1 (CNL, n = 5), AR (CNG, n = 4), CDK6 (CNG, n = 4), MET (CNG, n = 3), ERBB2 (mutation, n = 2; as speci ed above), LRP1B (CNL, n = 2) and FGFR2 (CNG, n = 1) (see Fig. 3).…”

Whole Exome Analysis to Select Targeted Therapies for Patients with Metastatic Breast Cancer – A Feasibility Study

“…In the other three cases, endocrine therapy was combined with either a CDK4/6 inhibitor or fulvestrant or HER2targeted therapy when the subtype changed during the course of the disease, and therefore probably showed a good effect of the respective therapy. Other GAs of clinical interest due to possible ineffectiveness [11,23,24,25,26] detected in our collective are: NF1 (CNL, n = 5), AR (CNG, n = 4), CDK6 (CNG, n = 4), MET (CNG, n = 3), HER2 (mutation, n = 2; as specified above), LRP1B (CNL, n = 2) and FGFR2 (CNG, n = 1) (see ▶ Fig. 2).…”

Targeted Sequencing of Plasma-Derived vs. Urinary cfDNA from Patients with Triple-Negative Breast Cancer

“…A study of Thai TNBC patients has reported KMT2C to be among the most frequently mutated genes in this population, found in 57.76% ( n = 116) of all cases [ 68 ]. In a study by Serio et al, KMT2C was among the 15 most altered genes and was more frequently altered in elderly TNBC patients (26%, n = 22) than in young patients [ 69 ]. Li et al investigated tissue samples of 17 Chinese TNBC patients with special morphologic patterns (STs).…”