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Publication Number
US-12410478-B2
Publication Date
2025-09-09
Expiration Date
Abstract
The invention generally relates to a molecular classification of disease predisposition and particularly to molecular markers for cancer predisposition and methods of use thereof.
Core Innovation
The invention relates to hereditary cancer gene panels for germline cancer predisposition testing. It describes extracting genomic DNA from a sample comprising germline cells of a patient and using nucleic acid probes that hybridize to genomic DNA molecules comprising coding regions of a plurality of test genes, including target genes such as APC, ATM, BARD1, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, PTEN, STK11, and TP53.
After hybridization, one or more amplification reactions amplify the nucleic acid molecules in the DNA mixture in the presence of primer pairs, and each primer pair generates amplification products comprising a portion of each target gene. The amplification products are sequenced, and the sequences are compared with one or more reference sequences for each target gene using alignment software.
The comparison determines whether the patient has germline mutations based on the presence of at least one insertion or deletion greater than 1,000 nucleotides in the sequences of the amplification products. The description also references reference sequences and transcript variants with exon coordinates, gene panel selection and clinical correlation to specific cancers and syndromes, and kits, probes, primer sets, and systems/software for interpreting sequence data and communicating risk.
Claims Coverage
The independent claim covers germline mutation detection by probe hybridization, primer-based amplification of target gene portions, sequencing, and alignment-based comparison to reference sequences with an insertion/deletion criterion. Dependent claims add reference-sequence definition, exon/intron flanking structure, personal and family risk factors, and quantitative target-gene composition constraints.
Probe hybridization to coding regions of gene panels
Hybridizing nucleic acid probes to genomic DNA molecules comprising the coding regions of a plurality of test genes, including target genes such as APC, ATM, BARD1, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, PTEN, STK11, and TP53.
Primer-pair amplification of portions of each target gene
Performing one or more amplification reactions in the presence of primer pairs, wherein each primer pair generates amplification products comprising a portion of each target gene.
Sequencing and alignment-based reference comparison
Sequencing the amplification products and comparing the sequences with one or more reference sequences of each target gene using alignment software.
Insertion/deletion criterion for germline mutation determination
Determining whether the patient has germline mutations in the target genes based on the presence of at least one insertion or deletion greater than 1,000 nucleotides in the sequences of the amplification products.
Reference sequences defined by an explicit target-gene table
Including reference sequences identified by the sequence of each target gene listed in the provided Entrez/Gene Symbol/SEQ ID NO table.
Exon plus intron-flanking sequence structure in amplification products
At least one amplification product includes an exon sequence portion and an intron sequence portion of at least 10 base pairs flanking one end of the exon sequence.
Second level risk-factor determination using personal and family risk factors
Determining whether the patient has at least one second level risk factor, including personal and family risk factors.
Quantitative panel composition threshold for target genes
The method is characterized by a set of target genes that make up at least 25% of the plurality of test genes.
The claim set focuses on panel-based germline mutation detection by probe hybridization to coding regions, amplification with primer pairs, sequencing of target-gene-containing products, and alignment-based comparison to reference sequences, using an insertion/deletion length threshold as the mutation criterion. Dependent claims further define reference sequences, exon/intron flanking structure, additional personal and family risk factors, and quantitative composition constraints on the target gene set.
Stated Advantages
Improved clinical sensitivity versus single-gene testing, reported in comparisons such as Panel D versus BRCA1/BRCA2 and Panel E versus MMR-gene testing.
Documented Applications
Germline cancer predisposition testing by detecting germline mutations in a hereditary cancer gene panel using sequencing and reference-sequence alignment.
Integration of additional personal and family risk factors with sequence-based mutation detection for risk likelihood and risk communication.
Use of hereditary cancer gene panels with specified gene-to-cancer/syndrome correlations to relate tested genes to cancers and syndromes.
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