Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T-cell lymphomas

Patent metadata

Field	Value
Publication number	US-9574241-B2
Application number	US-201414895287-A
Country	US
Kind code	B2
Filing date	Jun 3, 2014
Priority date	Jun 3, 2013
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing identified new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DN-MT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, new and recurrent, genetic defects are described including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.

First claim

What is claimed is:

1. A method, comprising
(a) providing a biological sample from a subject that has lymphoma;
(b) analyzing the biological sample to detect for presence of RHOA p.Glyl7Val mutation,
(c) determining that the subject has Peripheral T-Cell Lymphoma if RHOA p.Glyl7Val mutation, is detected in the biological sample and
(d) if it is determined that the subject has an increased risk of developing Peripheral T-Cell Lymphoma due to the presence of a mutation selected from the group consisting of FYN p.Leu174Arg, FYN p.Arg176Cys, and FYN p.Tyr531His, then prophylactically treating the subject for Peripheral T-Cell Lymphoma by administering a therapeutically effective amount of an SRC kinase inhibitor.

2. The method of claim 1 , wherein the biological sample is selected from the group consisting of lymphoma tumor, bone marrow, serum, blood, cerebrospinal fluid and plasma.

3. The method of claim 1 , wherein the subject is human.

4. The method of claim 1 , wherein the SRC kinase inhibitor is selected from the group consisting of Bosutinib (SKI-606); Saracatinib (AZD0530); Dasatinib (BMS354825); KX2-391; XL-228, JNJ-26483327, A 419259 trihydrochloride; AZM 475271; Damnacanthal, Herbimycin A, Lavendustin A, MNS, 1-Naphthyl PP1 D 166285 dihydrochloride, PP 1, PP 2, SRC I1, KX2-391 (KX01); and NVP-BHG712.

5. The method of claim 1 , further comprising:
(e) if it is determined that subject has Peripheral T-Cell Lymphoma and if the RHOA p.Glyl7Val mutation is present then determining that the Peripheral T-Cell Lymphoma has a 70% change of being angioimmunoblastic T-cell lymphoma.

Assignees

• Univ Columbia

Inventors

• Ferrando Adolfo
• Rabadan Raul
• Palomero Teresa

Classifications

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title