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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

Genomic similarities of synchronous DCIS and IDC(A) Overlapping somatic mutations between synchronous DCIS and IDC that share 243 identical somatic variants. (B) Comparison of numbers and categories of somatic mutations between synchronous DCIS and IDC. (C) Net frequency plots of copy number alterations across whole chromosomes for the synchronous DCIS (n = 5) and IDC (n = 5).
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Figure 2: Genomic similarities of synchronous DCIS and IDC(A) Overlapping somatic mutations between synchronous DCIS and IDC that share 243 identical somatic variants. (B) Comparison of numbers and categories of somatic mutations between synchronous DCIS and IDC. (C) Net frequency plots of copy number alterations across whole chromosomes for the synchronous DCIS (n = 5) and IDC (n = 5).

Mentions: Matched DCIS and IDC (synchronous DCIS and IDC) samples showed remarkably similar patterns in both somatic mutations and CNAs in many aspects (Figure 2). Average concordance rate of the mutations between synchronous DCIS and IDC was 53.8% (range, 19.8% – 82.0%), which was far higher than the inter-IDC concordance rate (average 0.6%) or inter-DCIS concordance rate (average 0.1%) (Figure 2A–2B, Table S1). More importantly, concordance rates for both TP53 and PIK3CA mutations, the most well-known mutation in breast cancers, between synchronous DCIS and IDC were 100% (Figure 3). For the CNAs, the average concordance rate was 76.6% (range, 46.2–93.1%) (Figure 2C), which was far higher than the inter-IDC (average 19.4%) or inter-DCIS concordance (average 18.5%) (Table S3). Of note, gains of AKT1, MYC and PIK3CA were present in both synchronous DCIS and IDC. In contrast, the gain of MET, and losses of PTEN, BRCA2 and TP53 were present in either one of the synchronous DCIS or IDC (Figure 4). All the 13 chromothripses in synchronous DCIS and IDC occurred in a pairwise fashion except one that occurred only in synchronous DCIS (case ID12-D) (Table S5). Since synchronous DCIS and IDC showed a high concordance, we grouped them together and termed them DCIS-IDC for comparison with pure DCIS samples.


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)

Genomic similarities of synchronous DCIS and IDC(A) Overlapping somatic mutations between synchronous DCIS and IDC that share 243 identical somatic variants. (B) Comparison of numbers and categories of somatic mutations between synchronous DCIS and IDC. (C) Net frequency plots of copy number alterations across whole chromosomes for the synchronous DCIS (n = 5) and IDC (n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Genomic similarities of synchronous DCIS and IDC(A) Overlapping somatic mutations between synchronous DCIS and IDC that share 243 identical somatic variants. (B) Comparison of numbers and categories of somatic mutations between synchronous DCIS and IDC. (C) Net frequency plots of copy number alterations across whole chromosomes for the synchronous DCIS (n = 5) and IDC (n = 5).
Mentions: Matched DCIS and IDC (synchronous DCIS and IDC) samples showed remarkably similar patterns in both somatic mutations and CNAs in many aspects (Figure 2). Average concordance rate of the mutations between synchronous DCIS and IDC was 53.8% (range, 19.8% – 82.0%), which was far higher than the inter-IDC concordance rate (average 0.6%) or inter-DCIS concordance rate (average 0.1%) (Figure 2A–2B, Table S1). More importantly, concordance rates for both TP53 and PIK3CA mutations, the most well-known mutation in breast cancers, between synchronous DCIS and IDC were 100% (Figure 3). For the CNAs, the average concordance rate was 76.6% (range, 46.2–93.1%) (Figure 2C), which was far higher than the inter-IDC (average 19.4%) or inter-DCIS concordance (average 18.5%) (Table S3). Of note, gains of AKT1, MYC and PIK3CA were present in both synchronous DCIS and IDC. In contrast, the gain of MET, and losses of PTEN, BRCA2 and TP53 were present in either one of the synchronous DCIS or IDC (Figure 4). All the 13 chromothripses in synchronous DCIS and IDC occurred in a pairwise fashion except one that occurred only in synchronous DCIS (case ID12-D) (Table S5). Since synchronous DCIS and IDC showed a high concordance, we grouped them together and termed them DCIS-IDC for comparison with pure DCIS samples.

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