PTEN Inactivation Rates in Endometrium

  Loss of PTEN function may be scored by mutation or deletions of the DNA coding for the PTEN gene on chromosome 10q23 (Table I), or by non-physiologic absence of the PTEN protein (Tables 2,3).  PTEN mutation rates in endometrial tissues are highly dependent on the case selection process, greatest in endometrioid (Type I) cancers compared to non-endometrioid (Type 2, papillary serous, clear cell) cancers (5).  Be sure to see the table of PTEN inactivation frequency by histopathologic diagnosis.  High prevalence PTEN mutation in otherwise "normal" endometrium suggests that progression efficiency is a major  modifier of cancer risk for those women with early premalignant disease.

 Greatest PTEN mutational rates of all, 83%(4), are seen in endometrioid adenocarcinomas which are preceded by a premalignant lesion (Table I).  This is strong evidence for association of PTEN loss of function with a multi-step progression model in which the premalignant phases(EIN) are already PTEN mutant (1-4).

 Table I: Sequence-Confirmed PTEN mutation rates(3).

Endometrial tissue diagnosis

PTEN mutations

No. of samples

Mutant, %

Endometrioid cancer

30

83%

Precancer (EIN)

29

55%

PTEN null glands are present in Normal, Premalignant, and Malignant Endometrium.   Immunohistochemistry has many advantages over DNA sequencing as a method of finding loss of PTEN function.  It is technically easier, permitting rapid processing of large series, and allows discovery of rare PTEN protein null glands unaffected by adjacent stroma or PTEN-intact glands.  Table 2 shows 43%, 56%, and 63% PTEN null rates, respectively, in 132 endometrial samples diagnosed as (normal) proliferative, unopposed estrogen exposed (Persistent proliferative) and EIN (4). PTEN mutation and/or deletion was confirmed in microdissected PTEN protein null glands of (normal) proliferative endometria, thereby confirming that loss of PTEN protein is caused by changes to the PTEN gene itself.  These findings were seen in a variety of clinical settings and specimen types as shown in Table 2.  Although the prevalence of PTEN-null glands was high amongst all diagnostic classes, there are dramatic changes in the physical morphology of these clones between diagnostic groups.

Table 2:  Clinicopathologic features of endometria by PTEN immunohistochemistry, and slide diagnosis(4).  

 

 

%  PTEN-null by Diagnosis

 

 

Proliferative

Persistent Proliferative

EIN

Total

Sample Type

 

Curettage

42.9%

54.5%

75.0 %

54.5 % (18/33)

Biopsy

42.9 %

56.7 %

59.3 %

51.5 % (51/99)

Clinical
indication for tissue sampling

 

bleeding

42.9 %

56.3 %

55.0 %

51.3 % (41/80)

infertility/recurrent abortion

41.7 %

0.0 %

100.0 %

46.2 % (6/13)

prior hyperplasia

0.0 %

0.0 %

71.4 %

75.0 % (6/8)

anatomic

50.0 %

100.0 %

100.0 %

62.5 % (5/8)

other

20 %

33.3 %

0.0 %

20.0 % (2/10)

unspecified

75.0 %

60.0 %

100 %

76.9 % (10/13)

Sex Hormone Source

 

Endogenous

42.9 %

55.9 %

64.3 %

51.7 % (61/118)

Exogenous

0.0 %

57.1 %

57.1 %

57.1 % (8/14)

Menopausal Status

 

Pre

42.9 %

57.1 %

66.7 %

51.8  % (58/112)

Post

0.00 %

50.0 %

57.1 %

55.0 % (11/20)

Total

 

42.9%(24/56)

56.1 %(23/41)

62.9%(22/35)

52.3 % (69/132)

PE Mutant Histo.jpg (101422 bytes)  Figure 1: PTEN Immunohistochemistry in endometrium. PTEN-null glands (black  arrowhead) appear pale green against dark brown staining of surrounding stroma in proliferative (left, Cases 339, 366), persistent proliferative (center, Cases 624, 496), and EIN (right, Cases 847, 593) endometria from six different patients. Brown PTEN-positive glands (white arrowhead) are present in proliferative and persistent proliferative examples for comparison. Scale bar is 500Ám.  

 PE Mutant Seq.jpg (31038 bytes)Figure 2: Sequence confirmed PTEN mutation in proliferative endometrium. Single-plex PCR and denaturing gradient gel electrophoresis of the exon 5 of PTEN gene. DNA from PTEN-null glands (NULL) have aberrantly migrating species (arrowheads) compared to PTEN expressing (POS) glands. Bidirectional (for, forward; rev, reverse) direct sequence confirmation of mutations is shown in panels below. PTEN immunohistochemistry of these two proliferative endometria is shown in Figure 1, left.

 

References:

  1. Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ, Ellenson LH. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 1998; 58(15):3254-3258.

  2. Maxwell GL, Risinger JI, Gumbs C, Shaw H, Bentley RC, Barrett JC et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58(12):2500-2503.

  3. Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92(11):924-930.

  4. Mutter GL, Ince TA, Baak JPA, Kust G, Zhou X, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res,6:4311-4314, 2001.

  5. Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 2000; 13(3):295-308.

 

Copyright 1998-2014 by George L. Mutter, MD.  All Rights Reserved