Albert Einstein College of Medicine

Other

New York University

Harry Ostrer

Johnny C Loke

Alexander Pearlman

Ishraq Alim, I

Heritable pathogenic variants in the mismatch repair (MMR) pathway, also known as Lynch Syndrome (LS), can lead to the development of colon cancer and other cancers. Following mismatch, a complex of proteins consisting of MLH1, MSH2, MSH6 and PMS2 translocate into the nucleus to signal recruitment of repair mechanisms. Flow cytometry-based, functional variant assays (FVAs), were developed to determine whether variants in these MMR repair genes and/or other related genes would augment the nuclear translocation of MLH1 and MSH2 and downstream nuclear phosphorylation of ATM and ATR in response to DNA mismatches. Each assay distinguished pathogenic variants in MMR repair genes (MLH1, MSH2, PMS2 and MSH6) from benign controls. The combination of multiple assays provided robust separation between heterozygous pathogenic variant carriers and benign controls. The ability to produce distinct molecular phenotypes by these assays suggest FVA assays of MMR pathways could be used to identify LS and associated risk of colon and other cancers and could act as an adjunct to MMR gene sequencing panels in categorizing variants.

Methods and compositions for diagnosing and treating, germline mismatch repair deficiencies, lynch syndrome and assessing germline risks of cancer

Heritable mutations in the BRCA1 and BRCA2 and other genes in the DNA double-strand break (DSB) repair pathway increase risk of breast, ovarian and other cancers. In response to DNA breaks, the proteins encoded by these genes bind to each other and are transported into the nucleus to form nuclear foci and initiate homologous recombination. Flow cytometry-based functional variant analyses (FVAs) were developed to determine whether variants in BRCA1 or other DSB repair genes disrupted the binding of BRCA1 to its protein partners, the phosphorylation of p53 or the transport of the BRCA1 complex to the nucleus in response to DNA damage. Each of these assays distinguished high-risk BRCA1 mutations from low-risk BRCA1 controls. Mutations in other DSB repair pathway genes produced molecular phenocopies with these assays. FVA assays may represent an adjunct to sequencing for categorizing VUS or may represent a stand-alone measure for assessing breast cancer risk.

Methods and compositions for determining the functional activity of DNA double strand break repair pathway molecules for assessing germline risk of cancer

A method of determining the risk of metastasis of breast or lung cancer in a human subject who has or had breast or lung cancer is disclosed herein. The method is based on detecting in a sample from the subject the number of copies per cell of genes and/or genomic regions of a metastatic gene signature set disclosed herein, and determining alternations in the number of copies per cell of the genes and/or genomic regions in the signature set, as compared to the number of copies per cell in non-cancer cells, thereby determining the risk of breast/lung cancer metastasis.

Robust genomic predictor of breast and lung cancer metastasis

Methods and compositions for assessing germline risk of cancer

Methods and compositions are disclosed for rapid functional analysis of gene variants based on analysis of protein-protein and protein-nucleic acid interactions.

Methods and compositions for rapid functional analysis of gene variants

Heritable mutations in the BRCA1 and BRCA2 and other genes in the DNA double-strand break (DSB) repair pathway increase risk of breast, ovarian and other cancers. In response to DNA breaks, the proteins encoded by these genes bind to each other and are transported into the nucleus to form nuclear foci and initiate homologous recombination. Flow cytometry-based functional variant analyses (FVAs) were developed to determine whether variants in BRCA1 or other DSB repair genes disrupted the binding of BRCA1 to its protein partners, the phosphorylation of p53 or the transport of the BRCA1complex to the nucleus in response to DNA damage. Each of these assays distinguished high-risk BRCA1 mutations from low-risk BRCA1 controls. Mutations in other DSB repair pathway genes produced molecular phenocopies with these assays. FVA assays may represent an adjunct to sequencing for categorizing VUS or may represent a stand-alone measure for assessing breast cancer risk.

A method of determining the risk of metastasis of prostate cancer in a human subject who has or had prostate cancer is disclosed herein. The method is based on detecting in a prostate sample from the subject the number of copies per cell of genes and/or genomic regions of a metastatic gene signature set disclosed herein, and determining alternations in the number of copies per cell of the genes and/or genomic regions in the signature set, as compared to the number of copies per cell in non-cancer cells, thereby determining the risk of prostate cancer metastasis.

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New York, NY, United States of America

Harry Ostrer