PTEN Changes

The most commonly altered gene is PTEN, a tumor suppressor gene which serves to modulate cell division rates and enable apoptosis (19). The proportion of endometrial carcinomas that demonstrate PTEN inactivation is dependent to a certain extent on case selection. The highest rate is 83%, seen in those sporadic endometrioid cancers associated with a coexisting or previous premalignant lesion (20). A functional link between endometrial carcinogenesis and PTEN inactivation is further supported by a 20% endometrial cancer rate in a constitutive murine PTEN knockout model (21). In humans

Initiation

Additional mutation

Malignant transformation

Fig. 2. A clonal model of endometrioid endometrial carcinogenesis. The first mutation which initiate carcinogenesis are within cells that maintain an appearance and behavior similar to normal, thus, their designation as "latent precancers." The earliest morphologically distinguished premalignant lesion, endometrial intraepithelial neoplasia are generated through additional mutation and clonal expansion into a histological focus with altered cytology and architecture. Malignant transformation from endometrial intraepithelial neoplasia to adenocarcinoma is driven by further mutation and acquisition of an aggressive phenotype. Nongenetic factors can act as positive or negative selection factors for clonal expansion and/or survival, thereby altering probability of progression.

Initiation

Additional mutation

Malignant transformation

Fig. 2. A clonal model of endometrioid endometrial carcinogenesis. The first mutation which initiate carcinogenesis are within cells that maintain an appearance and behavior similar to normal, thus, their designation as "latent precancers." The earliest morphologically distinguished premalignant lesion, endometrial intraepithelial neoplasia are generated through additional mutation and clonal expansion into a histological focus with altered cytology and architecture. Malignant transformation from endometrial intraepithelial neoplasia to adenocarcinoma is driven by further mutation and acquisition of an aggressive phenotype. Nongenetic factors can act as positive or negative selection factors for clonal expansion and/or survival, thereby altering probability of progression.

isolated PTEN inactivation is insufficient to induce endometrial carcinoma, requiring additional nongenetic and genetic factors to be invoked before progression to a malignant phase.

The earliest detected genetic changes and somatically acquired endometrial gland mutations in the PTEN tumor suppressor gene are not accompanied by any cytological or architectural modifications evident at the light microscopic level (Fig. 3) (22). This "latent precancer" phase is subclinical in every respect, falling below the threshold of detection using routine diagnostic methods, and without a highly increased prospective cancer risk. It is presence or absence of local and systemic selection factors for subsequent clonal expansion or involution, which stratify patients into risk groups. In the latent phase, mutated cells may participate in successive endometrial regeneration during the course of many menstrual cycles, and demonstrate normal morphogenesis in conjunction with associated stroma.

Another early event, i.e., inactivation of mismatch repair mechanisms that result in a microsatellite instability (MI) phenotype, might also take place before acquisition of a specific histological phenotype (10) and is seen in 15-20% of endometrioid cancers (11,23). Epigenetic silencing of the MLH1 gene through promoter methylation is the most common mechanism (24) of induction of MI. This form of genetic instability increases basal mutagenic rates, thereby accelerating acquisition of cumulative damage sufficient for malignant transformation. The majority of endometrioid carcinomas,

5.2. Latent (Preclinical) Phase of Carcinogenesis

Fig. 3. PTEN immunohistochemistry uncovers mutant glands devoid of histological change (latent precancer). Normal proliferative endometrium from a naturally cycling premenopausal woman in which two glands (pale) fail to express PTEN protein, in contrast to stroma and flanking (dark) glands. Microdissection of these nonexpressing glands show somatic genomic mutations in the PTEN gene, which are absent in the matched PTEN protein expressing glands. PTEN inactivation is not accompanied by changes in architecture or cytology. PTEN immunohistochemistry with antibody 6h2.1.

Fig. 3. PTEN immunohistochemistry uncovers mutant glands devoid of histological change (latent precancer). Normal proliferative endometrium from a naturally cycling premenopausal woman in which two glands (pale) fail to express PTEN protein, in contrast to stroma and flanking (dark) glands. Microdissection of these nonexpressing glands show somatic genomic mutations in the PTEN gene, which are absent in the matched PTEN protein expressing glands. PTEN inactivation is not accompanied by changes in architecture or cytology. PTEN immunohistochemistry with antibody 6h2.1.

however, do not demonstrate MI, so this should not be construed as either a necessary or even predominant, element of endometrial carcinogenesis.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment