Systems and methods for treating patients having a genetic predisposition to develop prostate cancer
Systems and methods for mitigating prostate cancer development are provided. Peripheral blood cells may be evaluated for the presence or quantity of gamma-H2AX foci, and/or for gene alterations encoding a protein with impaired or lack of function, for example, because the encoded protein is truncated, and correlating with prostate cancer development. Such nucleic acids may encode proteins from or peripheral to the DNA damage repair pathway and/or androgen receptor signaling pathway, or that are otherwise correlated with prostate cancer development. Such genes include one or more of AKR1C1, PALB2, APTX, BLM, BRCA1, CTBP1, DDB2, FANCA, FANCL, MBD5, MSH3, NEIL3, RAD51D, RAD54L2, SP1, TP53BP1, UBE2D3, UBE2V2, NRIP1, EFCAB6, CRISP3, PAPSS2, ATP6V0A2, ALG13, MGAT2, B3GAT3, DOLK, FLT3, ASXL1, KDR, or NOTCH2.
1 . A method for reducing the risk of developing prostate cancer in a human subject comprising:
(a) isolating peripheral blood lymphocytes from the human subject and treating at least a portion of the isolated peripheral blood lymphocytes with a low dose of an agent or radiation that induces double stranded breaks in DNA;
(b) quantifying a level of gamma-H2AX foci in the peripheral blood lymphocytes treated with the low dose of the agent or radiation;
(c) assaying nucleic acid molecules from the peripheral blood lymphocytes of (b) for the presence or absence of one or more altered genes, the one or more altered genes:
(i) comprising an ALG6 gene having an alteration in a splice site acceptor sequence; or
(ii) encoding one or more variant proteins selected from the group consisting of aprataxin (APTX) R56X, breast cancer 1 (BRCAI) Q356R, nei-like DNA glycosylase 3 (NEIL3) F460C, EF-Hand Calcium Binding Domain 6 (EFCAB6) Q1340Rfs*43, Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B 1) D218V, CYP1B1 T404Sfs*30, 3′-Phosphoadenosine 5′-Phosphosulfate Synthase 2 (PAPSS2) P454L, TSC Complex Subunit 1 (TSC1) H732Y, Bone Gamma-Carboxyglutamate Protein (BGLAP) C74X, Fanconi Anemia complementation group L (FANCL) T367Nfs*13, mutS homolog 3 (MSH3) I929T, ATPase H+ Transporting V0 Subunit A2 (ATP6VOA2) K103N, helicase ARIP4/androgen receptor-interacting protein 4 (RAD54L2) I730F, Nuclear Receptor Interacting Protein 1 (NRIP1) E91G, NRIP1 V1079F, methyl-CpG-binding domain protein 5 (MBD5) A326V, C-terminal binding protein 1 (CTBP1) P421L, Sodium Voltage-Gated Channel Alpha Subunit 11 (SCN11A) F1626Y, Hydroxy-Delta-5-Steroid Dehydrogenase (HSD3B1) V224-Y225insH, F-Box And WD Repeat Domain Containing 7 (FBXW7) E117del, partner and localizer of BRCA2 (PALB2) E1002Tfs*4, PALB2 G998E, Fanconi Anemia complementation group A (FANCA) S1088F, Bloom Syndrome RecQ Like Helicase (BLM) P868L, Cysteine Rich Secretory Protein 3 (CRISP3) A197V, TGFB Induced Factor Homeobox 1 (TGIF1) W30X, Kinase Insert Domain Receptor (KDR) p.A1065T, ElaC Ribonuclease Z 2 (ELAC2) S490A, Myosin Heavy Chain 14 (MYH14) A882V, Acetylglucosaminyltransferase (ALG13), E795del, ubiquitin-conjugating enzyme E2 D3 (UBE2D3), Talin 1 (TLN1) L1539V, Protein Inhibitor Of Activated STAT 3 (PIAS3) R67W, aldo-keto reductase family 1, member C1 (AKR1C1) S221N, damage-specific DNA binding protein 2 (DDB2) R47del, Acetyl-CoA Carboxylase Alpha (ACACA) R1182W, Histone Deacetylase 9 (HDAC9) Y199C, Mannoside Acetylglucosaminyltransferase 2 (MGAT2) 1160S, tumor suppressor p53 binding protein 1 (TP53BP1) I455-P456del, Insulin Degrading Enzyme (IDE) G72S, IDE M254T, Nuclear Receptor Corepressor 2 (NCOR2) R1794Q, Glutathione S-Transferase Alpha 1 (GSTA1) E168K, ubiquitin-conjugating enzyme E2 V2 (UBE2V2) R101Q, Additional Sex Combs Like 1 (ASXL1) R573W, Sp1 transcription factor (SP1) G240R, Beta-1,3-Glucuronyltransferase 3 (B3GAT3) R60G, Dolichol Kinase (DOLK) MINfs, Fms-Like Tyrosine Kinase 3 (FLT3) Y842C, Sulfotransferase 1E1 (SULTIE1) W27C, NOTCH2 F1209V, RAD51 paralog D (RAD51D) E223G and Ribonuclease L (RNASEL) G59S;
(d) determining that the human subject is predisposed to developing prostate cancer based on:
(i) the quantified level of gamma-H2AX foci in the peripheral blood lymphocytes of step (b) being at least 50% higher than a reference number of gamma-H2AX foci obtained using lymphocytes from a healthy individual; and
(ii) the assaying step of (c) identifying the presence of the one or more altered genes; and
(e) treating the human subject determined to be predisposed to developing prostate cancer according to step (d) with a treatment regimen comprising:
(i) prostatectomy, androgen deprivation therapy, a PARP inhibitor, or one or more of diet management, vitamin supplementation, nutritional supplementation, exercise, psychological counseling, social counseling, education, and regimen compliance management; and,
(ii) an enhanced regimen for monitoring prostate cancer development, wherein the enhanced regimen is more frequent or more aggressive than monitoring provided to average-risk individuals;
wherein the human subject is the subject identified as predisposed in step (d).
2 . The method of claim 1 , wherein the agent that induces double stranded breaks in DNA comprises aphidicolin or etoposide.
3 . The method of claim 1 , wherein the one or more altered genes comprise rare variants.
4 . The method of claim 3 , wherein the rare variants comprise rare single nucleotide variants.
5 . The method of claim 1 , wherein the one or more altered genes comprise a combination of rare variants and non-rare variants.
6 . The method of claim 5 , wherein the rare variants comprise rare single nucleotide variants.
7 . The method of claim 1 , wherein the one or more altered genes encode a stop codon that results in a truncated protein with no functionality following expression of the protein.
8 . The method of claim 1 , wherein the one or more altered genes encode one or more variant proteins selected from the group consisting of aldo-keto reductase family 1, member C1 (AKR1C1) S221N, partner and localizer of BRCA2 (PALB2) E1002Tfs*4, PALB2 G998E, aprataxin (APTX) R56X, bloom syndrome RecQ Like Helicase (BLM) P868L, breast cancer 1 (BRCA1) Q356R, C-terminal binding protein 1 (CTBP1) P421L, damage-specific DNA binding protein 2 (DDB2) R47del, Fanconi Anemia complementation group A (FANCA) S1088F, Fanconi Anemia complementation group L (FANCL) T367Nfs*13, methyl-CpG-binding domain protein 5 (MBD5) A326V, mutS homolog 3 (MSH3) I929T, nei-like DNA glycosylase 3 (NEIL3) F460C, RAD51 paralog D (RAD51D) E223G, helicase ARIP4/androgen receptor-interacting protein 4 (RAD54L2) I73OF, Sp1 transcription factor (SP1) G240R, tumor suppressor p53 binding protein 1 (TP53BP1) 1455-P456del, ubiquitin-conjugating enzyme E2 D3 (UBE2D3), and ubiquitin-conjugating enzyme E2 V2 (UBE2V2) R101Q.
9 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising PALB2 E1002Tfs*4 or PALB2 G998E.
10 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising FANCL T367Nfs*13, MSH3 I929T, or RAD54L2 I730F.
11 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising BLM P868L, PALB2 E1002Tfs*4, PALB2 G998E, or FANCA S1088F.
12 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising APTX R56X or NEIL3 F460C.
13 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising APTX R56X, NEIL3 F460C, or BRCA1 Q356R.
14 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising TP53BP1 1455-P456del.
15 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising TP53BP1 1455-P456del or BRCA1 Q356R.
16 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising DDB2 R47del.
17 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising CTBP1 P421L.
18 . The method of claim 8 , wherein the one or more altered genes encode a protein comprising AKR1C1 S221N.
19 . The method of claim 1 , wherein the one or more altered genes encode a protein comprising NRIP1 E91G, NRIP1 V1079F, EFCAB6 Q1340Rfs*43, or CRISP3 A197V.
20 . The method of claim 1 , wherein the one or more altered genes encode a protein comprising PAPSS2 P454L, ATP6VOA2 K103N, ALG13 E795del, MGAT2 I160S, B3GAT3 R60G, DOLK MINfs, FLT3 Y842C, ASXL1 R573W, KDR pA1065T, or NOTCH2 F1209V.
21 . The method of claim 20 , wherein the one or more altered genes encode a protein comprising PAPSS2 P454L.
22 . The method of claim 20 , wherein the one or more altered genes encode a protein comprising FLT3 Y842C, ASXL1 R573W, KDR p.A1065T, or NOTCH2 F1209V.