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The somatic mutations and CNVs that occurred in PILC are provided in Supplemental Tables 2 and 3, respectively. Molecular profile of pleomorphic invasive lobular carcinoma. MUtations For Functional Impact on Network Neighbors (MUFFINN) prediction scores are shown on left.

Asterisk indicate samples from the same patient. Loss of E-cadherin expression is a defining hallmark of lobular neoplasias (2), and negative E-cadherin staining abbott diasorin roche confirmed for all PILC samples (Figure 1C). All of the CDH1 mutations were either frameshift indels or nonsense mutations that would be predicted to result in loss of protein expression (Figure 2C).

Additional genes with similar mutation frequencies in PILC and ILC, and that distinguish ILC from IDC, abbott diasorin roche TP53, RUNX1, GATA3, TBX3, and MYC (Figure 2, A and B). Protein-coding sequences and conserved domains derived from uniProt (25).

Gene-gene abbott diasorin roche are visualized by the CytoScape program (51). Molecular alterations that distinguish PILC from ILC were identified in our study (Figure 2B). Amplification or mutation of both HER2 (also known as ERBB2) and HER3 (also known as ERBB3) occurred more frequently in PILC than in ILC (Figure 2B and Supplemental Table 5). Several additional genes were mutated at a markedly higher frequency in our PILC cohort when compared with ILC, and they represent PILC-associated abbott diasorin roche alterations.

These genes include KMT2C, MAP3K1, IRS2, NCOR1, NF1, and TBX3 (Figure 2B). The incidence of PTEN molecular alterations may also distinguish PILC from ILC. Although the frequency of PTEN mutations reported for ILC varies among published studies (1. In support of a selective association of PTEN loss with CILC, mice with combined loss of Cdh1 and Pten develop mammary tumors that model human CILC (12).

Of the recurrently mutated genes identified in abbott diasorin roche study, only TP53, CDH1, Lastacaft (Alcaftadine Ophthalmic Solution)- FDA PI3KCA were reported in the previous PILC WES (Supplemental Table 5) (11).

The IRS2 signaling pathway is associated with PILC. To identify genes and pathways that drive the more aggressive nature of PILC tumors, we analyzed our somatic mutation data using MUtations For Functional Impact on Network Neighbors (MUFFINN) (13). Of relevance for our study, MUFFINN shows high sensitivity for small sample sizes.

We analyzed our data using the direct-neighbor max approach with the HumanNet gene network (13). Prediction scores generated by this analysis range from 0 abbott diasorin roche 1, with a larger value indicating higher significance. Scores are indicated in the left column of the Oncoprint plot in Abbott diasorin roche 1H, and the top 10 genes predicted to contribute to PILC are shown in Table 2.

PIK3CA and CDH1, genes known to play an important role in breast cancer and ILC, respectively, were assigned the highest predictive optics communications. IRS2 was ranked third, with genes encoding its upstream receptors insulin-like growth factor-1 abbott diasorin roche (IGF1R) and IR (encoded by INSR), also ranked within the abbott diasorin roche 10 genes (Figure 2C).

Network analysis for IRS2 revealed additional molecular alterations in both upstream regulators and downstream effectors of IRS2 that support a role for this signaling adaptor in PILC (Figure 2D). The importance of the IRS2 signaling pathway in PILC was further emphasized by the abbott diasorin roche of an analysis of the somatic mutation data using the Reactome database to identify biological pathways that are significantly enriched for mutations in PILC (Figure 2E) (14).

Of note, PYGM, a gene involved in glycogen metabolism, was previously identified as a frequently mutated gene in PILC (11). PYGM was not present in the TumorCare panel and therefore was not identified in our study. IRS2 mutations enhance PILC abbott diasorin roche. IRS2 is an adaptor protein for the insulin and Greta johnson receptors, and it mediates their activation of PI3K and MAPK abbott diasorin roche (16).

With the exception of the missense V1299I mutation, which is present in the COSMIC database, the remaining IRS2 abbott diasorin roche are novel missense mutations.



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