Genes frequently altered in pancreatic neuroendocrine tumors

Patent metadata

Field	Value
Publication number	US-10144971-B2
Application number	US-201213977810-A
Country	US
Kind code	B2
Filing date	Jan 4, 2012
Priority date	Jan 4, 2011
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten non-familial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. Remarkably, the most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

First claim

We claim:

1. A method, comprising:
extracting nucleic acids from pancreatic neuroendocrine tumor of an individual;
amplifying and sequencing exomic sequences of the extracted nucleic acids in genes TSC2, PIK3CA, IRS1, and PTEN;
detecting a mutation in an exomic sequence of at least one of TSC2, PIK3CA, PTEN, or IRS1; and
administering to the individual an mTOR inhibitor when the mutation is detected.

2. The method of claim 1 , wherein the mTOR inhibitor is evorolimus.

3. The method of claim 1 , wherein the mTOR inhibitor is rapamycin.

4. The method of claim 1 , wherein the mTOR inhibitor is deforolimus.

5. The method of claim 1 , wherein the mTOR inhibitor is temsirolimus.

6. The method of claim 1 , additionally comprising amplifying and sequencing exomic sequences in genes TSC2, PIK3CA, IRS1, and PTEN from normal tissue of the individual.

7. The method of claim 1 , wherein the amplifying or sequencing is performed using at least one primer selected from the group consisting of SEQ ID NOs: 63-83, 208-228, 84-92, 229-237, 104-145, and 249-290.

8. The method of claim 1 , wherein the mutation comprises an indel, frameshift, or nonsense mutation.

9. The method of claim 1 , wherein the mutation comprises a somatic mutation.

10. The method of claim 1 , wherein the nucleic acids are extracted from resected tumor.

11. The method of claim 1 , wherein the nucleic acids are extracted from a biopsy of the tumor.

12. The method of claim 1 , further comprising the step of enriching the nucleic acids extracted from the tumor for exomic sequences.

13. The method of claim 7 , wherein evorolimus is administered to the individual.

14. A method, comprising:
extracting nucleic acids from a plasma sample of an individual with a pancreatic neuroendocrine tumor;
amplifying and sequencing exomic sequences of the extracted nucleic acids in genes TSC2, PIK3CA, IRS1, and PTEN;
detecting a mutation in an exomic sequence of at least one of TSC2, PIK3CA, PTEN, or IRS1, and
administering to the individual an mTOR inhibitor when the mutation is detected.

15. The method of claim 14 , wherein the amplifying or sequencing is performed using at least one primer selected from the group consisting of SEQ ID NOs: 63-83, 208-228, 84-92, 229-237, 104-145, and 249-290.

16. The method of claim 14 , wherein the mutation comprises an indel, frameshift, or nonsense mutation.

17. The method of claim 14 , wherein the mutation comprises a somatic mutation.

18. The method of claim 14 , wherein the mTOR inhibitor is evorolimus.

19. The method of claim 14 , wherein the mTOR inhibitor is rapamycin.

20. The method of claim 14 , wherein the mTOR inhibitor is deforolimus.

21. The method of claim 14 , wherein the mTOR inhibitor is temsirolimus.

22. The method of claim 14 , further comprises the step of enriching the nucleic acids extracted from the plasma sample for exomic sequences.

Assignees

• Vogelstein Bert
• Kinzler Kenneth W
• Velculescu Victor
• Diaz Luis
• Papadopoulos Nikolas
• Jiao Yuchen
• Hruban Ralph
• Univ Johns Hopkins

Inventors

• Vogelstein Bert
• Kinzler Kenneth W
• Velculescu Victor
• Diaz Luis
• Papadopoulos Nikolas
• Jiao Yuchen
• Hruban Ralph

Classifications

• G01N33/57525

  of the liver or pancreas · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title