Project description:We analysed a cohort of breast papillary lesions cases with (n=4) or without (n=7) co-existed cancer for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan® MIP arrays. Cases included pure papilloma (withoout cancer) (n=7), papilloma cases synchronous with cancer (n=4). We have analysed copy number calling from these samples including carcinoma components of synchronous cases in order to understand the precursor relationship as well any biomarker for progression from papillary lesions to carcinoma.
Project description:Our purpose is to identify candidate genes involved in the early steps of breast cancer metastasis and examine their pro-invasive functions both in vitro and in vivo. A percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this “breast to breast” metastasis. These mutations might promote breast cancer distant spread. The pro-invasive functions of a candidate metastasis gene were assessed in vitro by its abilities to promote proliferation, migration and invasion and in vivo as tumor xenografts in immunocompromised mice or a syngeneic orthotopic mouse breast cancer model. RNAseq analysis was performed to probe the transcription programs modulated by this candidate metastasis gene. SIVA1-D160N was one somatic mutation acquired in the breast to breast metastasis. Over-expression of SIVA1-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA1-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA1-D160N promoted anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA1-D160N in 4T1 cells increased mammary gland tumor growth as well as liver metastasis. We conclude clonally related bilateral breast cancers represent a novel system to investigate metastasis and revealed a role of SIVA1-D160N in breast cancer metastasis.
Project description:As organ-specific models of breast cancer bone metastasis do not exist, we established a novel breast cancer line was established from the ER-/PR-/HER2- bone metastasis from a breast cancer patient. This cell line was characterized and compared to the primary tumour and/or normal mammary epithelial cells with regards to phenotypes (i.e. marker expression), gene expression and copy number variation.
Project description:As organ-specific models of breast cancer bone metastasis do not exist, we established a novel breast cancer line was established from the ER-/PR-/HER2- bone metastasis from a breast cancer patient. This cell line was characterized and compared to the primary tumour and/or normal mammary epithelial cells with regards to phenotypes (i.e. marker expression), gene expression and copy number variation.
Project description:As organ-specific models of breast cancer bone metastasis do not exist, we established a novel breast cancer line was established from the ER-/PR-/HER2- bone metastasis from a breast cancer patient. This cell line was characterized and compared to the primary tumour and/or normal mammary epithelial cells with regards to phenotypes (i.e. marker expression), gene expression and copy number variation.
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.
