Systems and methods for diagnosing a predisposition to develop cancer

Abstract

Systems, methods, and computer readable media for diagnosing or characterizing a genetic predisposition to develop cancer, including cancers of the BAP1 cancer syndrome, are provided. Nucleic acids comprising a germline nucleic acid sequence encoding the BRCA1 associated protein 1 (BAP1) are sequenced or probed to determine if the nucleic acid sequence includes alterations that predispose a subject to develop cancer.

We claim: 
     
         1 . A system for determining a predisposition to develop BAP1 cancer syndrome, comprising: a data structure comprising one or more BRCA1 associated protein 1 (BAP1) germline nucleic acid sequences having one or more alterations in the germline nucleic acid sequence indicative of a predisposition to develop BAP1 cancer syndrome, provided that the one or more alterations exclude the insertion of an A between nucleotides 52,437,842 and 52,437,843 of human chromosome 3; one or more BAP1 germline nucleic acid sequences that do not have the one or more alterations; and a processor programmed to compare sequences of nucleic acids encoding BAP1 obtained from a human being with the BAP1 germline nucleic acid sequences in the data structure. 
     
     
         2 . The system of  claim 1 , wherein the one or more alterations encode a truncated BAP1 protein or result in nonsense-mediated decay of BAP1-encoding mRNA transcribed from the altered germline nucleic acid sequence. 
     
     
         3 . The system of  claim 1 , wherein the one or more alterations are located at the BAP1 locus in in human chromosome segment 3p21.1. 
     
     
         4 . The system of  claim 1 , wherein one or more alterations are selected from the group consisting of a C to T substitution in Exon 16 of the BAP1 gene, an A to G substitution two nucleotides upstream of the 3′ end of Intron 6 of the BAP1 gene, a deletion of five nucleotides from and a substitution of one nucleotide at the 3′ end of Exon 3 of the BAP1 gene, a deletion of twenty five nucleotides in Exon 4 of the BAP1 gene, a deletion of a C in Exon 13 of the BAP1 gene, a deletion of four nucleotides from Exon 14 of the BAP1 gene, a T to G substitution in Exon 9 of the BAP1 gene, and a deletion of a T in Exon 4 of the BAP1 gene. 
     
     
         5 . The system of  claim 4 , wherein the C to T substitution at Exon 16 occurs in the germline nucleic acid sequence at location corresponding to position 52,436,624 of human chromosome 3. 
     
     
         6 . The system of  claim 4 , wherein the A to G substitution occurs at a location in the germline nucleic acid sequence at a location corresponding to position 52,441,334 of human chromosome 3. 
     
     
         7 . The system of  claim 4 , wherein the deletion of five nucleotides occurs in the germline nucleic acid sequence at a location corresponding to positions 52,443,570 to 52,443,574 of human chromosome 3, and the substitution of one nucleotide in the 3′ end of Exon 3 is a G to A substitution and occurs in the germline nucleic acid sequence at a location corresponding to position 52,443,575 of human chromosome 3. 
     
     
         8 . The system of  claim 4 , wherein the deletion of twenty five nucleotides in Exon 4 occurs in the germline nucleic acid sequence at a location corresponding to positions 52,442,507 to 52,442,531 of human chromosome 3. 
     
     
         9 . The system of  claim 4 , wherein the deletion of a C in Exon 13 occurs in the germline nucleic acid sequence at a location corresponding to position 52,437,444 of human chromosome 3. 
     
     
         10 . The system of  claim 4 , wherein the deletion of four nucleotides from Exon 14 occurs in the germline nucleic acid sequence at a location corresponding to positions 52,437,159 to 52,437,162 of human chromosome 3. 
     
     
         11 . The system of  claim 4 , wherein the T to G substitution occurs in the germline nucleic acid sequence at a location corresponding to position 52,440,329 of human chromosome 3. 
     
     
         12 . The system of  claim 4 , wherein the deletion of a T in Exon 4 occurs in the germline nucleic acid sequence at a location corresponding to position 52,442,605 of human chromosome 3. 
     
     
         13 . The system of  claim 1 , wherein the BAP1 cancer syndrome includes one or more of malignant mesothelioma, uveal melanoma, and cutaneous melanoma. 
     
     
         14 . The system of  claim 1 , further comprising a computer network connection. 
     
     
         15 . The system of  claim 1 , further comprising a sequencer for determining the sequence of the nucleic acids encoding BAP1 obtained from the subject. 
     
     
         16 . The system of  claim 1 , further comprising an output for providing results of the comparison to a user. 
     
     
         17 . The system of  claim 1 , wherein the germline nucleic acid sequences comprise genomic DNA, mRNA, or a cDNA obtained from mRNA. 
     
     
         18 . The system of  claim 1 , further comprising executable code for causing the processor to calculate a risk score the human subject to develop one or more of malignant mesothelioma, breast cancer, ovarian cancer, pancreatic cancer, kidney cancer, cutaneous melanoma, or uveal melanoma based on a comparison of sequences of nucleic acids encoding BAP1 obtained from the subject with the BAP1 germline nucleic acid sequences in the data structure. 
     
     
         19 . A method for identifying an alteration in the germline BRCA1 associated protein 1 (BAP1) nucleic acid sequence that predisposes a subject having the alteration to develop BAP1 cancer syndrome, comprising:
 (a) determining the sequence of a nucleic acid encoding BAP1 in a tissue sample obtained from a human subject;   (b) entering the determined sequence from step (a) into the system of  claim 1 ;   (c) causing the processor of the system to compare the determined sequence from step (a) with one or more of the BAP1 germline nucleic acid sequences in the data structure; and   (d) determining whether the determined sequence from step (a) has the alteration based on the comparison from step (c).   
     
     
         20 . The method of  claim 19 , wherein the BAP1 cancer syndrome includes one or more of malignant mesothelioma, uveal melanoma, and cutaneous melanoma. 
     
     
         21 . A method for determining whether a subject has a predisposition to develop BAP1 cancer syndrome, comprising:
 (a) determining the sequence of a nucleic acid encoding BAP1 in a tissue sample obtained from a human subject;   (b) entering the determined sequence from step (a) into the system of  claim 1 ;   (c) causing the processor of the system to compare determined sequence from step (a) with one or more of the BAP1 germline nucleic acid sequences in the data structure;   (d) determining whether the determined sequence from step (a) has one or more alterations in the BAP1 germline nucleic acid sequence indicative of a predisposition to develop BAP1 cancer syndrome based on the comparison from step (c); and optionally   (e) treating the subject with a treatment regimen capable of inhibiting development of BAP1 cancer syndrome, wherein the treatment regimen comprises one or more of administering to the subject an effective mount of BAP1 protein, reducing exposure of the subject to carcinogenic mineral fibers, and reducing exposure of the subject to ultraviolet radiation.   
     
     
         22 . The method of  claim 21 , wherein the BAP1 cancer syndrome includes one or more of malignant mesothelioma, uveal melanoma, and cutaneous melanoma.