Differential Mutations in Matched Primary and Metastatic Colorectal Cancers
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ABSTRACT: This study compares DNA mutations detected in matched primary and metastatic colorectal cancer samples from 18 individuals across 1,321 genes. We found many more mutations were shared between tumor pairs (avg. 33.3 mutations/tumor) than were discordant (avg. 2.3 mutations / tumor). Nearly all tumors showed at least one discordance, and these were observed in genes known to be involved in colorectal cancer progression. Therefore, although primary and metastatic colorectal tumors are highly genetically concordant, evidence exists for discordance, which has clinical implications especially in situations of chemotherapy resistance or insensitivity.
SECONDARY ACCESSION(S): PRJNA314364PRJNA314365
REPOSITORIES: dbGaP
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Project description:Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear. We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that in many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner. We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis. We analyzed 16 tissue samples from four patients. For each patient we analyzed the DNA of a primary colon tumor sample, a normal colon tissue sample, a metastatic liver tumor sample and a normal liver tissue sample. The normal colon and normal liver samples serve as a control for the primary and metastatic tumor samples.
2011-10-11 | E-GEOD-32711 | biostudies-arrayexpress
Project description:<p>Molecular profiling for somatic mutations that predict response to anti-EGFR therapy in colorectal cancer (CRC) has become standard practice. However, abundant tissue from metastatic lesions is not always available from patients with metastatic CRC. Concerns involving genetic heterogeneity between primary and metastatic lesions have called into question the suitability of profiling primary tumors in patients with metastatic disease. Further, the identification of discordant mutations between matched primary and metastatic tumors would be of biological interest for the delineation of biomarkers of tumor progression and metastasis.</p> <p>To explore the degree of genetic heterogeneity between matched primary and metastatic tumors in CRC, we performed whole genome sequencing of four patient "trios" comprised of a primary colon tumor, a liver metastasis, and matched normal (non-cancerous) tissue. Somatic mutations and indels were called in each tumor and compared between primary and metastatic lesions.</p>
| phs000790 | dbGaP
Project description:Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear. We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that in many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner. We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis.
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Project description:Differential Mutations In Matched Primary and Metastatic Colorectal Cancers
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Project description:Current knowledge of prostate cancer genomes is largely based on relatively small patient cohorts using single modality analysis platforms. Here we report concordant assessment of DNA copy number, mRNA and microRNA expression and focused exon resequencing in prostate tumors from 218 patients with primary or metastatic prostate cancer with a median of 5 years clinical follow-up, now made available as a public resource. Mutations in known, commonly mutated oncogenes and tumor suppressor genes such as PIK3CA, KRAS, BRAF and TP53 are present but generally rare. However, integrative analysis of mutations with copy number alterations (CNAs) and expression changes reveal alterations in the PI3K, RAS/RAF and androgen receptor (AR) pathways in nearly all metastatic samples and in a higher frequency of primary samples than previously suspected based on single-gene studies. Other new findings include evidence that the nuclear receptor coactivator NCOA2 functions as a driver oncogene in ~20 percent of primaries. Tumors with the androgen-driven TMPRSS2-ERG fusion were significantly associated with a small, previously unrecognized, prostate-specific 3p14 deletion that, through mRNA expression and resequencing analysis, implicates FOXP1, RYBP and SHQ1 as candidate cooperative tumor suppressors. Comparison of transcriptome and DNA copy number data from primary tumors for prognostic impact revealed that CNAs robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. In sum, this integrative genomic analysis of a substantial cohort of tumors clarifies the role of several known cancer pathways in prostate cancer, implicates several new ones, reveals a previously unappreciated role for CNAs in prognosis and provides a blueprint for clinical development of pathway inhibitors. Human prostate samples were profiled on Agilent microRNA V2 arrays per manufacturer's instructions.
2010-06-24 | E-GEOD-21036 | biostudies-arrayexpress
Project description:Current knowledge of prostate cancer genomes is largely based on relatively small patient cohorts using single modality analysis platforms. Here we report concordant assessment of DNA copy number, mRNA and microRNA expression and focused exon resequencing in prostate tumors from 218 patients with primary or metastatic prostate cancer with a median of 5 years clinical follow-up, now made available as a public resource. Mutations in known, commonly mutated oncogenes and tumor suppressor genes such as PIK3CA, KRAS, BRAF and TP53 are present but generally rare. However, integrative analysis of mutations with copy number alterations (CNAs) and expression changes reveal alterations in the PI3K, RAS/RAF and androgen receptor (AR) pathways in nearly all metastatic samples and in a higher frequency of primary samples than previously suspected based on single-gene studies. Other new findings include evidence that the nuclear receptor coactivator NCOA2 functions as a driver oncogene in ~20 percent of primaries. Tumors with the androgen-driven TMPRSS2-ERG fusion were significantly associated with a small, previously unrecognized, prostate-specific 3p14 deletion that, through mRNA expression and resequencing analysis, implicates FOXP1, RYBP and SHQ1 as candidate cooperative tumor suppressors. Comparison of transcriptome and DNA copy number data from primary tumors for prognostic impact revealed that CNAs robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. In sum, this integrative genomic analysis of a substantial cohort of tumors clarifies the role of several known cancer pathways in prostate cancer, implicates several new ones, reveals a previously unappreciated role for CNAs in prognosis and provides a blueprint for clinical development of pathway inhibitors.
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Project description:We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss (SCNAs). The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar SCNA patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number of alterations. Genomically, colorectal and metastatic liver tumors were very similar. However, in a subgroup of patients, there were genetic variations in liver metastases in the loss of DNA mismatch repair genes. Copy number analysis of Affymetrix CytoScanHD arrays was performed for 15 primary colorectal carcinoma and 15 samples of their matched liver metastases. 15 normal samples prepared from each of the patient was used as the reference for the study. Nexus Copy number 6.1 software was used for somatic copy number alteration analysis.
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Project description:We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss (SCNAs). The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar SCNA patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number of alterations. Genomically, colorectal and metastatic liver tumors were very similar. However, in a subgroup of patients, there were genetic variations in liver metastases in the loss of DNA mismatch repair genes.
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