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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

Abundance of somatic mutations and copy number alterations (CNAs) in 6 pure DCIS, 5 synchronous DCIS and 5 synchronous IDC genomes(A) The numbers of somatic mutations are shown for the 6 pure DCIS (top) (PD17, PD18, PD19, PD21, PD22 and PD23), 5 synchronous DCIS (middle) (ID1-D, ID3-D, ID4-D, ID6-D and ID12-D) and 5 synchronous IDC (bottom) (ID1-I, ID3-I, ID4-I, ID6-I and ID12-I) genomes with respect to the 6 categories (insets). (B) The numbers of copy number alterations (CNAs) with log2 ratios of > 0.3 or < −0.3 together with genome-wide heatmaps of probe-level intensities (log2 ratios) are shown. (blue: gain, red: loss).
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Figure 1: Abundance of somatic mutations and copy number alterations (CNAs) in 6 pure DCIS, 5 synchronous DCIS and 5 synchronous IDC genomes(A) The numbers of somatic mutations are shown for the 6 pure DCIS (top) (PD17, PD18, PD19, PD21, PD22 and PD23), 5 synchronous DCIS (middle) (ID1-D, ID3-D, ID4-D, ID6-D and ID12-D) and 5 synchronous IDC (bottom) (ID1-I, ID3-I, ID4-I, ID6-I and ID12-I) genomes with respect to the 6 categories (insets). (B) The numbers of copy number alterations (CNAs) with log2 ratios of > 0.3 or < −0.3 together with genome-wide heatmaps of probe-level intensities (log2 ratios) are shown. (blue: gain, red: loss).

Mentions: To find genomic differences between early and invasive breast cancer lesions, pure DCIS without any invasive component from six patients, and synchronous DCIS and IDC from five patients were analyzed (Table 1). Mean coverage of the sequencing depth was 72X for both the tumor and the normal genomes. A total of 1,130 somatic mutations (1,007 point mutations and 123 indels (Table S1)) were identified in the 16 lesions (29–137 somatic mutations (median of 50.5) per lesion). We categorized the breast lesions into three groups: pure DCIS, synchronous DCIS and synchronous IDC and identified a median of 36.5 (range, 29–58), 82 (range, 37–137) and 110 mutations (range, 33–134) in each, respectively (Figure 1A). None of the mutation numbers, subtypes or spectra was significantly different between the three groups (Figure S1A–S1D, Table S2), but we observed a trend towards synchronous DCIS and IDC harboring more mutations than pure DCIS (p = 0.065). Consistent with previous data in breast cancer [10, 11], the C/G to T/A transition was the most common type across the cases, making up about 50% of the entire mutation (Figure S1C–S1D).


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)

Abundance of somatic mutations and copy number alterations (CNAs) in 6 pure DCIS, 5 synchronous DCIS and 5 synchronous IDC genomes(A) The numbers of somatic mutations are shown for the 6 pure DCIS (top) (PD17, PD18, PD19, PD21, PD22 and PD23), 5 synchronous DCIS (middle) (ID1-D, ID3-D, ID4-D, ID6-D and ID12-D) and 5 synchronous IDC (bottom) (ID1-I, ID3-I, ID4-I, ID6-I and ID12-I) genomes with respect to the 6 categories (insets). (B) The numbers of copy number alterations (CNAs) with log2 ratios of > 0.3 or < −0.3 together with genome-wide heatmaps of probe-level intensities (log2 ratios) are shown. (blue: gain, red: loss).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Abundance of somatic mutations and copy number alterations (CNAs) in 6 pure DCIS, 5 synchronous DCIS and 5 synchronous IDC genomes(A) The numbers of somatic mutations are shown for the 6 pure DCIS (top) (PD17, PD18, PD19, PD21, PD22 and PD23), 5 synchronous DCIS (middle) (ID1-D, ID3-D, ID4-D, ID6-D and ID12-D) and 5 synchronous IDC (bottom) (ID1-I, ID3-I, ID4-I, ID6-I and ID12-I) genomes with respect to the 6 categories (insets). (B) The numbers of copy number alterations (CNAs) with log2 ratios of > 0.3 or < −0.3 together with genome-wide heatmaps of probe-level intensities (log2 ratios) are shown. (blue: gain, red: loss).
Mentions: To find genomic differences between early and invasive breast cancer lesions, pure DCIS without any invasive component from six patients, and synchronous DCIS and IDC from five patients were analyzed (Table 1). Mean coverage of the sequencing depth was 72X for both the tumor and the normal genomes. A total of 1,130 somatic mutations (1,007 point mutations and 123 indels (Table S1)) were identified in the 16 lesions (29–137 somatic mutations (median of 50.5) per lesion). We categorized the breast lesions into three groups: pure DCIS, synchronous DCIS and synchronous IDC and identified a median of 36.5 (range, 29–58), 82 (range, 37–137) and 110 mutations (range, 33–134) in each, respectively (Figure 1A). None of the mutation numbers, subtypes or spectra was significantly different between the three groups (Figure S1A–S1D, Table S2), but we observed a trend towards synchronous DCIS and IDC harboring more mutations than pure DCIS (p = 0.065). Consistent with previous data in breast cancer [10, 11], the C/G to T/A transition was the most common type across the cases, making up about 50% of the entire mutation (Figure S1C–S1D).

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