Spatial Genomics With Co-Registered Histology

Abstract

Three dimensional tumor volume is analyzed spatially by genomics and transcriptomics, or both. Thin sections are cut with a microtome using a tape transfer technique so that the thin tissue sections remain without any distortion or deformation, in sequence relative to their position in the original tissue, so that a three-dimensional coordinate system can be anchored to each tissue section. Small samples of tissue are extracted or punched from very precise locations in the supports using the coordinate system as a grid, with known x,y,z location, and subjected to genomic sequencing. Sequence data is analyzed using the three dimensional coordinate system, so that the original tissue is thereby analyzed as a three dimensional system volume. At the same time, alternate tissue sections (or the same sections from which samples have been extracted with sample punches) can be subjected to staining and imaging to do histochemical analysis.

What is claimed is: 
     
         1 - 34 . (canceled) 
     
     
         35 . A sectioning unit comprising:
 a microtome configured to create a set of ordered, sequential sections cut from a biological specimen, each section being assigned a two dimensional (x,y) coordinate system to provide for spatial localization of features identified on the sections; and   a transport system configured to adhere to each section and transfer each section for analysis, a third coordinate system (z) being assigned along a depth of the biological specimen to allow for ordered sequential sections.   
     
     
         36 . The sectioning unit of  claim 35 , wherein the biological specimen is configured to be prepared having a blockface. 
     
     
         37 . The sectioning unit of  claim 36 , wherein the two dimensional (x, y) coordinate system is co-planar to the blockface of the biological specimen. 
     
     
         38 . The sectioning unit of  claim 36 , wherein the third coordinate system (z) is perpendicular to the blockface of the biological specimen. 
     
     
         39 . The sectioning unit of  claim 36 , wherein the transport system utilizes a support configured to adhere to the blockface of the biological specimen. 
     
     
         40 . The sectioning unit of  claim 39 , wherein the support adheres to each section to create an un-distorted support-mounted section. 
     
     
         41 . The sectioning unit of  claim 39 , wherein the support comprises a tape. 
     
     
         42 . The sectioning unit of  claim 39 , wherein the support is labelled with a value n of said third coordinate system z. 
     
     
         43 . The sectioning unit of  claim 41 , wherein the transport system is configured to transfer the sections from the microtomes to one or more slides. 
     
     
         44 . The sectioning unit of  claim 40 , wherein a subset of the un-distorted support-mounted sections is configured to be processed to identify features of the biological specimen by histochemical staining. 
     
     
         45 . The sectioning unit of  claim 40 , wherein a subset of the un-distorted support-mounted sections is configured to be processed using nucleic acid sequencing to generate genomic data. 
     
     
         46 . The sectioning unit of  claim 40 , wherein a first subset of the un-distorted support-mounted sections is configured to be analyzed and a second subset of the un-distorted support-mounted sections is configured to be stored. 
     
     
         47 . The sectioning unit of  claim 40 , wherein a first subset of the un-distorted support-mounted sections is configured to be analyzed using a first analysis method and a second subset of the un-distorted support-mounted sections is configured to be analyzed using a second analysis method. 
     
     
         48 . The sectioning unit of  claim 40 , wherein a first subset of the un-distorted support-mounted sections is configured to be analyzed using a first analysis method and a second subset of the un-distorted support-mounted sections is configured to be analyzed using a second analysis method. 
     
     
         49 . The sectioning unit of  claim 35 , wherein the transport system is automated. 
     
     
         50 . The sectioning unit of  claim 35 , further comprising a fiducial element system configured to provide reference points on each section to establish the two dimensional coordinate system and the three dimensional coordinate system using at least one fiducial marker embedded in each section. 
     
     
         51 . The sectioning unit of  claim 49 , wherein at least three fiducial markers are embedded in each section to establish the two dimensional (x,y) coordinate system. 
     
     
         52 . A system for creating a three-dimensional representation of a biological specimen, comprising:
 a depository system configured to store information about a set of ordered, sequential sections cut from a biological specimen, the stored information including genomic sequencing data related to the sections which each have a two dimensional coordinate system to provide for spatial localization of features identified on the sections and a third dimensional coordinate system perpendicular to the sections to allow for ordered sequential sections;   analysis-storage system associated with the depository system that allows a user to identify features of the specimen;   wherein the features include a spatial distribution of cells of specific morphologies or cells exhibiting identifiable characteristics under specific stains.   
     
     
         53 . The system of  claim 52 , wherein the depository system is configured to store the set of ordered, sequential sections. 
     
     
         54 . The system of  claim 52 , wherein a first subset of the sections is configured to be analyzed using a first analysis method and a second subset of the sections is configured to be analyzed using a second analysis method.