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Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer.

Kim SY, Jung SH, Kim MS, Baek IP, Lee SH, Kim TM, Chung YJ, Lee SH - Oncotarget (2015)

Bottom Line: We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC.Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations.Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, The Catholic University of Korea, Seoul.

ABSTRACT
Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of suggested genomic status of pure DCIS, synchronous DCIS and IDCDevelopment of pure DCIS requires essential genetic driver alterations, to which more genetic alterations are added for progression to synchronous DCIS-IDC. No significant genomic difference between IDC and synchronous DCIS suggest that they are genetically at the same stage with just intratumoral heterogeneity or minimal genetic changes during progression to IDC.
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Figure 6: Schematic representation of suggested genomic status of pure DCIS, synchronous DCIS and IDCDevelopment of pure DCIS requires essential genetic driver alterations, to which more genetic alterations are added for progression to synchronous DCIS-IDC. No significant genomic difference between IDC and synchronous DCIS suggest that they are genetically at the same stage with just intratumoral heterogeneity or minimal genetic changes during progression to IDC.

Mentions: In summary, pure DCIS is a neoplastic lesion that already harbors some driver alterations, but needs more drivers to become an invasive disease (Figure 6). Such early fixation of some driver mutations provides rationale for careful clinical management of pure DCIS. Our findings also indicate that neither a single gene nor a recurrent group of genes determines whether pure DCIS cells progress to IDC. We also found that the genomic features of DCIS associated with IDC were closer to IDC than pure DCIS. No significant genomic difference between IDC and synchronous DCIS suggest a possibility that these two histologically distinct lesions are genetically at the same stage, but show just intratumoral genetic heterogeneity. Another possibility is that during progression to IDC there are subtle genetic changes that may not be easily differentiated (Figure 6). Both possibilities suggest that even a histologically early lesion (DCIS) associated with IDC should be considered a possibly invasive lesion at the genomic level. By looking at all the evidence together, it might be possible to determine whether newly found DCIS after surgery is a residual tumor or newly developed pure DCIS. Finally, the association of PR-negativity and increased genomic burden may provide clues for further subclassification of breast cancers, enhancing diagnosis and management.


Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer.

Kim SY, Jung SH, Kim MS, Baek IP, Lee SH, Kim TM, Chung YJ, Lee SH - Oncotarget (2015)

Schematic representation of suggested genomic status of pure DCIS, synchronous DCIS and IDCDevelopment of pure DCIS requires essential genetic driver alterations, to which more genetic alterations are added for progression to synchronous DCIS-IDC. No significant genomic difference between IDC and synchronous DCIS suggest that they are genetically at the same stage with just intratumoral heterogeneity or minimal genetic changes during progression to IDC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480702&req=5

Figure 6: Schematic representation of suggested genomic status of pure DCIS, synchronous DCIS and IDCDevelopment of pure DCIS requires essential genetic driver alterations, to which more genetic alterations are added for progression to synchronous DCIS-IDC. No significant genomic difference between IDC and synchronous DCIS suggest that they are genetically at the same stage with just intratumoral heterogeneity or minimal genetic changes during progression to IDC.
Mentions: In summary, pure DCIS is a neoplastic lesion that already harbors some driver alterations, but needs more drivers to become an invasive disease (Figure 6). Such early fixation of some driver mutations provides rationale for careful clinical management of pure DCIS. Our findings also indicate that neither a single gene nor a recurrent group of genes determines whether pure DCIS cells progress to IDC. We also found that the genomic features of DCIS associated with IDC were closer to IDC than pure DCIS. No significant genomic difference between IDC and synchronous DCIS suggest a possibility that these two histologically distinct lesions are genetically at the same stage, but show just intratumoral genetic heterogeneity. Another possibility is that during progression to IDC there are subtle genetic changes that may not be easily differentiated (Figure 6). Both possibilities suggest that even a histologically early lesion (DCIS) associated with IDC should be considered a possibly invasive lesion at the genomic level. By looking at all the evidence together, it might be possible to determine whether newly found DCIS after surgery is a residual tumor or newly developed pure DCIS. Finally, the association of PR-negativity and increased genomic burden may provide clues for further subclassification of breast cancers, enhancing diagnosis and management.

Bottom Line: We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC.Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations.Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, The Catholic University of Korea, Seoul.

ABSTRACT
Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.

No MeSH data available.


Related in: MedlinePlus