Deckwirth Vivi, Hundi Sruthi, Hytönen Marjo K, Hannula Sari, Ellonen Pekka, Björkenheim Pia, Sukura Antti, Lohi Hannes
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
BMC Cancer. 2024 Dec 18;24(1):1524. doi: 10.1186/s12885-024-13239-w.
Breast cancer (BC) is the most common cancer in women. Likewise, canine mammary tumors (CMT) represent the most common cancer in intact female dogs and develop in the majority spontaneously. Similarities exist in clinical presentation, histopathology, biomarkers, and treatment. However, CMT subtype-specific genomic background is less investigated. Here, we assess the genetic etiology of two histomorphological (HM) subtypes with BC counterparts, the CMT invasive ductal simple solid carcinoma (SC) and comedocarcinoma (CC), and compare the results with BC data.
Groups of 11-13 transformed ductal luminal epithelial cells were laser-capture microdissected from snap-frozen invasive mammary SC and CC subtypes of one intact female dog. HM unaffected lobular luminal epithelial cells were controls. Single-cell whole genome libraries were generated using PicoPLEX and sequenced to compare the subtypes' somatic coding variant landscapes with each other and with BC data available in COSMIC-CGC and KEGG. Furthermore, HM and immunohistochemical (IHC) subtype characteristics were compared with the genomic results.
The CC had six times more variants than the SC. The SC showed variants in adherens junction genes and genes of the MAPK, mTOR and NF-kappa-B signaling pathways. In the CC, the extracellular matrix (ECM) receptor interaction, cell adhesion, PI3K-Akt and cGMP-PKG pathways were enriched, reflecting the higher cellular malignancy. Affected pathways in both CMT subtypes overlapped with BC pathways in KEGG. Additionally, we identified ATP6V1C2, GLYATL3, CARMIL3, GATAD2B, OBSCN, SIX2, CPEB3 and ZNF521 as potential new subtype-distinct driver genes. Furthermore, our results revealed biomarker alterations in IHC in the basal/myoepithelial cell layer without respective genetic mutations, suggesting changes to their complex signaling pathways, disturbed regulative feedback loops or other silencing mechanisms.
This study contributes to understanding the subtype-specific molecular mechanisms in the canine mammary invasive ductal simple SC and CC, and revealed subtype-specific molecular complexity for phenotypically similar characteristics. Several affected genes and signaling pathways overlapped with BC indicating the potential use of CMT as model for BC. Our findings emphasize the need for thorough characterization of cancer specimens with respect to translational cancer research, but also how insight into tumor heterogeneity will be crucial for the development of targeted prognostics and therapeutic interventions.
乳腺癌（BC）是女性中最常见的癌症。同样，犬乳腺肿瘤（CMT）是未绝育雌性犬中最常见的癌症，大多数为自发发生。在临床表现、组织病理学、生物标志物和治疗方面存在相似之处。然而，CMT亚型特异性基因组背景的研究较少。在此，我们评估了两种组织形态学（HM）亚型与乳腺癌对应亚型，即CMT浸润性导管单纯实体癌（SC）和粉刺癌（CC）的遗传病因，并将结果与乳腺癌数据进行比较。
从一只未绝育雌性犬的速冻浸润性乳腺SC和CC亚型中，通过激光捕获显微切割11 - 13个转化的导管腔上皮细胞群。HM未受影响的小叶腔上皮细胞作为对照。使用PicoPLEX生成单细胞全基因组文库并进行测序，以比较各亚型的体细胞编码变异图谱，并与COSMIC - CGC和KEGG中可用的乳腺癌数据进行比较。此外，将HM和免疫组织化学（IHC）亚型特征与基因组结果进行比较。
CC的变异比SC多六倍。SC在黏着连接基因以及MAPK、mTOR和NF - κB信号通路的基因中显示出变异。在CC中，细胞外基质（ECM）受体相互作用、细胞黏附、PI3K - Akt和cGMP - PKG通路富集，反映出更高的细胞恶性程度。两种CMT亚型中受影响的通路与KEGG中的乳腺癌通路重叠。此外，我们将ATP6V1C2、GLYATL3、CARMIL3、GATAD2B、OBSCN、SIX2、CPEB3和ZNF521鉴定为潜在的新的亚型特异性驱动基因。此外，我们的结果揭示了基底/肌上皮细胞层中IHC的生物标志物改变，但没有相应的基因突变，这表明其复杂信号通路发生了变化、调节反馈回路受到干扰或存在其他沉默机制。
本研究有助于理解犬乳腺浸润性导管单纯SC和CC中的亚型特异性分子机制，并揭示了表型相似特征的亚型特异性分子复杂性。一些受影响的基因和信号通路与乳腺癌重叠，表明CMT作为乳腺癌模型的潜在用途。我们的发现强调了在转化癌症研究中对癌症标本进行全面表征的必要性，同时也强调了深入了解肿瘤异质性对于开发靶向预后和治疗干预措施的关键作用。
