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Publication Number
US-11104956-B2
Publication Date
2021-08-31
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 a hereditary-cancer gene panel framework that sequences patient germline DNA to analyze defined panels of cancer predisposition genes. The framework includes extracting germline genomic DNA and determining coding regions of test genes, including sequencing the exons and intronic flanks, using reference transcripts and exon coordinates for comparison. The analyzed results are used to identify germline deficiencies and mutations in the relevant hereditary-cancer genes.
The framework correlates the presence or absence of detected germline deficiencies with increased or decreased risk for specific cancers and syndromes, including HBOC and Lynch syndrome, as described in Table 4. It uses matched gene lists and subpanels as panel definitions (Panels A–Q), along with reference sequence variants for alignment against the amplification or sequencing results. The document also describes systems/computer programs for risk assessment and provides gene-to-cancer/syndrome association outputs.
The document further describes sequencing and enrichment components, including kits, probe sets, primer pairs, and microarrays, together with validation examples. The validation results state increased clinical sensitivity for HBOC (Panel D versus BRCA1/2) and for Lynch syndrome (Panel E versus MMR genes), using mutation prevalence and sensitivity improvements in the described examples. The disclosed components are tied to hereditary-cancer panel analysis and subsequent clinical outputs.
Claims Coverage
The partial content includes one independent claim with multiple dependent claims. The independent claim combines mutation detection, probe-based hybridization to a test gene library, amplification and sequencing, and comparison to reference sequences, with dependent claims adding reference-sequence definition, exon and flanking-intron representation, and optional risk-factor determination and coverage thresholds.
Treatment regimen administration based on detected deleterious germline mutations
A method of administering a treatment regimen to a patient by extracting genomic DNA from germline cells, detecting whether a deleterious germline mutation is present using target gene sequencing comparisons, and administering the treatment regimen if a deleterious germline mutation in at least one of BRCA1, BRCA2, PTEN, and TP53 is detected. The treatment regimen includes performing a bilateral mastectomy.
Probe-based hybridization to a test gene library including target genes
Forming a mixture by hybridizing nucleic acid probes in a library to nucleic acid molecules in the genomic DNA, where the nucleic acid molecules comprise the coding regions of a plurality of test genes including target genes comprising APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN1, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53.
Amplification, sequencing, and alignment comparison against reference sequences
Performing one or more amplification reactions using one or more primer pairs to generate amplification products, determining the sequences of the amplification products, and comparing the sequences with one or more reference sequences using alignment software.
The independent claim covers conditional treatment-regimen administration, including bilateral mastectomy, based on detection of deleterious germline mutations in specified genes, using probe-hybridization to a test gene library, amplification and sequencing of target gene portions, and comparison to reference sequences with alignment software.
Stated Advantages
Increased clinical sensitivity for HBOC is stated for Panel D versus BRCA1/2.
Increased clinical sensitivity for Lynch syndrome is stated for Panel E versus MMR genes.
Mutation prevalence and sensitivity improvements are stated in the validation examples.
Documented Applications
Risk assessment and determination of hereditary cancer risk for HBOC and Lynch syndrome using hereditary-cancer gene panel sequencing and correlation of detected germline deficiencies and mutations to cancer/syndrome associations.
Clinical decision output supporting administration of a treatment regimen that includes performing a bilateral mastectomy when specified deleterious germline mutations are detected in BRCA1, BRCA2, PTEN, and TP53.
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