Malignant Mesothelioma Susceptibility As A Result Of Germline Leucine-Rich Repeat Kinase 2 (LRRK2) Alterations
AssigneeInstitute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center
InventorsJoseph R. Testa, Mitchell Cheung
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Abstract
The present disclosure provides methods of treating a subject having malignant mesothelioma, methods of identifying subjects having an increased risk of developing malignant mesothelioma, methods of detecting human Leucine-Rich Repeat Kinase 2 (LRRK2) variant nucleic acid molecules, and LRRK2 variant nucleic acid molecules.
Claims50
A method of identifying a subject having an increased risk for developing malignant mesothelioma, wherein the method comprises:
- determining or having determined the presence or absence of a Leucine-Rich Repeat Kinase 2 (LRRK2) variant nucleic acid molecule encoding an LRRK2 polypeptide in a biological sample obtained from the subject;
- wherein:
- when the subject does not have an LRRK2 variant nucleic acid molecule, then the subject does not have an increased risk for developing malignant mesothelioma;
- and
- when the subject is heterozygous or homozygous for an LRRK2 variant nucleic acid molecule, then the subject has an increased risk for developing malignant mesothelioma.
A method of treating a subject with a therapeutic agent that treats or inhibits malignant mesothelioma, wherein the subject has malignant mesothelioma, the method comprising the steps of:
- determining whether the subject has a Leucine-Rich Repeat Kinase 2 (LRRK2) variant nucleic acid molecule encoding an LRRK2 polypeptide by:
- obtaining or having obtained a biological sample from the subject;
- and
- performing or having performed an assay on the biological sample to determine if the subject has a genotype comprising the LRRK2 variant nucleic acid molecule;
- and
- when the subject does not have an LRRK2 variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits malignant mesothelioma in a standard dosage amount;
- and
- when the subject is heterozygous or homozygous for an LRRK2 variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits malignant mesothelioma in an amount that is the same as or greater than a standard dosage amount;
- wherein the presence of a genotype having the LRRK2 variant nucleic acid molecule encoding the LRRK2 polypeptide indicates the subject has an increased risk of developing malignant mesothelioma.
A method of detecting a human Leucine-Rich Repeat Kinase 2 (LRRK2) variant nucleic acid molecule in a subject comprising assaying a sample obtained from the subject to determine whether a nucleic acid molecule in the sample comprises a nucleotide sequence comprising a deletion of the nucleotides AAAGGTAAGG (SEQ ID NO:3) located at positions corresponding to positions 97,182 to 97,191 according to SEQ ID NO:1, or the complement thereof.
An isolated alteration-specific probe or alteration-specific primer comprising at least about 15 nucleotides, wherein the alteration-specific probe or alteration-specific primer comprises a nucleotide sequence which is complementary to a portion of a nucleotide sequence encoding a human Leucine-rich repeat kinase 2 (LRRK2) polypeptide, wherein the portion comprises positions corresponding to:
- positions 97,182 to 97,191 according to SEQ ID NO:1, or the complement thereof, or
- positions 97,181 to 97,190 according to SEQ ID NO:2, or the complement thereof.
A molecular complex comprising an alteration-specific primer or an alteration-specific probe hybridized to a genomic nucleic acid molecule comprising a nucleotide sequence encoding a human Leucine-Rich Repeat Kinase 2 (LRRK2) polypeptide, wherein the alteration-specific primer or the alteration-specific probe is hybridized to:
- the nucleotides AAAGGTAAGG (SEQ ID NO:
- 3) located at positions corresponding to positions 97,182 to 97,191 according to SEQ ID NO:
- 1, or the complement thereof;
- or
- the nucleotides AAAATCAATT (SEQ ID NO:4) located at positions corresponding to positions 97,181 to 97,190 according to SEQ ID NO:2, or the complement thereof.
An isolated nucleic acid molecule comprising a nucleotide sequence encoding a human Leucine-Rich Repeat Kinase 2 (LRRK2) polypeptide, wherein the nucleotide sequence comprises a deletion of the nucleotides AAAGGTAAGG (SEQ ID NO:3) located at positions corresponding to positions 97,182 to 97,191 according to SEQ ID NO:1, or the complement thereof.
A therapeutic agent that treats or inhibits malignant mesothelioma for use in the treatment of malignant mesothelioma in a subject having a genomic nucleic acid molecule having a nucleotide sequence encoding a Leucine-Rich Repeat Kinase 2 (LRRK2) polypeptide, wherein the nucleotide sequence comprises a deletion of the nucleotides AAAGGTAAGG (SEQ ID NO:3) located at positions corresponding to positions 97,182 to 97,191 according to SEQ ID NO:
- 1, or the complement thereof.
A therapeutic agent that treats or inhibits malignant mesothelioma for use in the preparation of a medicament for treating malignant mesothelioma in a subject having a genomic nucleic acid molecule having a nucleotide sequence encoding a Leucine-Rich Repeat Kinase 2 (LRRK2) polypeptide, wherein the nucleotide sequence comprises a deletion of the nucleotides AAAGGTAAGG (SEQ ID NO:3) located at positions corresponding to positions 97,182 to 97,191 according to SEQ ID NO:1, or the complement thereof.
Dependencies are inferred from the claim text.