Type I And Type Ii Tumors Are Characterized By Unique Molecular Features

Because serous carcinoma is the most common type of ovarian carcinoma, this discussion is focussed on low- and high-grade serous carcinomas as they represent the prototypes of type I and type II carcinomas, respectively. Both low- and high-grade serous carcinomas can be distinguished by unique molecular genetic alterations. Among

Table 1

Precursors and Molecular Genetic Alterations of Type I and Type II Tumors of the Ovary

Known molecular

Type I tumors Precursorsa genetic alterations

Low-grade serous carcinoma

Mucinous carcinoma

Endometrioid carcinoma

Clear cell carcinoma

Malignant Brenner (transitional) tumor

Type II tumors High-grade serous carcinoma

Serous cystadenoma/adenofibroma Atypical proliferative serous tumor Intraepithelial low-grade carcinoma Mucinous cystadenoma Atypical proliferative mucinous tumor Intraepithelial carcinoma Endometriosis Endometrioid adenofibroma Atypical proliferative endometrioid tumor

Intraepithelial carcinoma

Endometriosis

Clear cell adenofibroma

Atypical proliferative clear cell tumor

Intraepithelial carcinoma

Brenner tumor

Atypical proliferative Brenner tumor

Precursors Not yet identified

Undifferentiated carcinoma Malignant mixed mesodermal tumor

(carcinosarcomas)

Not yet identified Not yet identified

BRAF and KRAS mutations (~67%)

KRAS mutations (>60%)

LOH or mutations in

PTEN (20%) P-catenin gene mutations (16-54%) KRAS mutations (<10%) Microsatellite instability

(13-50%) KRAS mutations (5-16%) Microsatellite instability

(~13%) TGF-P RII mutation (66%)b Not yet identified

Known molecular genetic alterations p53 mutations (50-80%) Amplification and overepxression of HER2/neu gene (10%-20%) and AKT2 gene (12-18%) Inactivation of p16 gene

(10-17%) Not yet identified p53 mutations (>90%)

LOH, loss of heterozygosity; TGF, transforming growth factor.

a Atypical proliferative serous tumors and intraepithelial low-grade serous carcinoma have been termed "serous borderline" tumors in the literature. Similarly, for mucinous, endometrioid, clear cell, and Brenner tumors, atypical proliferative tumor, and intraepithelial carcinoma have been combined and designated "borderline tumor" in the literature.

^Based on preliminary results analyzing three cases (61).

them, the most well-studied molecular alterations are mutations in KRAS and BRAF oncogenes in low-grade serous carcinoma and mutations in p53 tumor-suppressor gene in high-grade serous carcinoma. KRAS and BRAF genes are the upstream regulators in the RAS/RAF/MEK/ERK/MAP signal transduction pathway, which plays a critical role

Mouse Ovarian Tumor

Fig. 1. Schematic representation of the dualistic model depicting the development of ovarian serous carcinomas, the most common type of ovarian cancer. Low-grade serous carcinoma represents the prototypic type I tumor and develops in a stepwise fashion from an atypical proliferative tumor through an intraepithelial or in situ stage of low-grade serous carcinomas (both of these tumors qualified as "borderline") before becoming invasive. These tumors are associated with frequent KRAS or BRAF mutations. High-grade serous carcinoma represents the prototypic type II tumor and develops from the ovarian surface epithelium or inclusion cysts without morphologically recognizable intermediate stages. KRAS and BRAF mutations have not been found in any of these neoplasms (14,19,68). CIN: chromosomal instability.

Fig. 1. Schematic representation of the dualistic model depicting the development of ovarian serous carcinomas, the most common type of ovarian cancer. Low-grade serous carcinoma represents the prototypic type I tumor and develops in a stepwise fashion from an atypical proliferative tumor through an intraepithelial or in situ stage of low-grade serous carcinomas (both of these tumors qualified as "borderline") before becoming invasive. These tumors are associated with frequent KRAS or BRAF mutations. High-grade serous carcinoma represents the prototypic type II tumor and develops from the ovarian surface epithelium or inclusion cysts without morphologically recognizable intermediate stages. KRAS and BRAF mutations have not been found in any of these neoplasms (14,19,68). CIN: chromosomal instability.

in the transmission of growth signals into the nucleus (18). Oncogenic mutations in BRAF and KRAS result in constitutive activation of this pathway and contribute to neoplastic transformation. Recent studies (14,19) have demonstrated that KRAS mutations at codons 12 and 13 occur in 35% of invasive low-grade serous carcinomas and 33% of borderline tumors (atypical proliferative tumor and intraepithelial low-grade carcinoma), but not in high-grade serous carcinomas. Similarly, BRAF mutations at codon 599 occur in 30% of low-grade serous carcinomas and 28% of borderline tumors, but not in high-grade serous carcinomas (19). Accordingly, mutations in either KRAS or BRAF were found in 65% of invasive low-grade serous carcinomas and in 68% of serous borderline tumors (atypical proliferative tumors and intraepithelial low-grade serous carcinomas). In contrast, neither of the genes is mutated in high-grade serous carcinomas (Fig. 2). It is of interest that BRAF mutations were found only in tumors with wild-type KRAS and vice versa (19). The mutually exclusive nature of BRAF mutations at codon 599 and KRAS mutations at codons 12 and 13 in ovarian carcinoma is consistent with similar findings in melanoma and colorectal carcinoma (20,21), and lends support to the view that KRAS and BRAF mutations have an equivalent effect on tumorigenesis. Mutations of KRAS and BRAF appear to occur very early in the development of low-grade serous carcinoma. To investigate how early mutations of KRAS

Braf And Kras Mutually Exclusive

BRAF and KRAS Mutations (%) p53 Mutations (%)

Fig. 2. Mutational analysis of KRAS, BRAF, and p53 in ovarian serous tumors. (A) Mutations in either KRAS (black bars) or BRAF (gray bars) occur frequently in both serous borderline tumors and invasive low-grade serous carcinomas. The mutations are not detected in all high-grade serous carcinomas examined based on the previous study (19) and additional cases. (B) Mutations in p53 are frequent in high-grade serous carcinoma, but are less frequent in serous borderline tumors and invasive low-grade serous carcinomas.

BRAF and KRAS Mutations (%) p53 Mutations (%)

Fig. 2. Mutational analysis of KRAS, BRAF, and p53 in ovarian serous tumors. (A) Mutations in either KRAS (black bars) or BRAF (gray bars) occur frequently in both serous borderline tumors and invasive low-grade serous carcinomas. The mutations are not detected in all high-grade serous carcinomas examined based on the previous study (19) and additional cases. (B) Mutations in p53 are frequent in high-grade serous carcinoma, but are less frequent in serous borderline tumors and invasive low-grade serous carcinomas.

and BRAF occur in the development of serous borderline tumors, Ho et al. compared the mutational status of KRAS and BRAF in both SBTs and the adjacent epithelium from cystadenomas, the presumed precursor of SBTs. In that study, three of eight SBTs contained mutant BRAF and four SBTs contained mutant KRAS. All specimens with mutant BRAF harbored wild-type KRAS and vice versa. Thus, seven (88%) of eight SBTs contained either KRAS or BRAF mutations. The same mutations detected in SBTs were identified in the cystadenoma epithelium adjacent to the serous borderline tumor (SBTs) in six (86%) of seven informative cases. As compared with SBTs, the cystade-noma epithelium like ovarian surface epithelium lacks cytological atypia. The aforementioned findings provide cogent evidence that mutations of KRAS and BRAF occur in the epithelium of cystadenomas adjacent to SBTs and strongly suggest that they are very early events in tumorigenesis, preceding the development of SBT (22).

In contrast to low-grade serous carcinoma where mutations in p53 are rare, mutations in p53 are common in high-grade serous carcinomas. Most studies have shown that approx 50-80% of advanced stage, presumably high-grade, serous carcinomas have mutant p53 (23-28). It has also been reported that mutant p53 is present in 37% of stage I and II, presumably high-grade serous carcinomas (29). In a study of very early microscopic stage I serous carcinomas in ovaries removed prophylatically from women who were BRCA heterozygotes, overexpression of p53, and mutation of p53 were found in all early invasive high-grade serous carcinomas as well as in the adjacent "dysplastic" surface epithelium (30). It is likely that inherited mutations in BRCA genes predispose the ovarian surface epithelium and inclusion cysts to neoplastic transformation through an increase in genetic instability. Although, sporadic ovarian carcinomas were not analyzed in this study, the clinical and pathological features of BRCA-linked ovarian carcinomas and their sporadic counterparts are indistinguishable, suggesting that their histogenesis is similar. Thus, although the molecular genetic findings are preliminary, they suggest that conventional high-grade serous carcinoma, in its very earliest stage resembles advanced stage serous carcinoma at the molecular as well as at the morphological level. Similar to high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) also demonstrate p53 mutations in almost all analyzed cases (31-33). It has been reported that the same p53 mutations occur in the epithelial and the mesenchymal components (31). Moreover, the fact that pure carcinomatous areas are often associated with sarcomatous components suggests a common derivation of both the epithelial and the mesenchymal components in these neoplasms (34). The finding that metastases from these tumors nearly always are made up of carcinoma, has led investigators to suggest that malignant mixed mesodermal tumors are metaplastic carcinomas.

Besides p53 mutations, high-grade serous carcinomas demonstrate other molecular genetic changes including amplification of HER-2/neu tyrosine kinase gene (35), amplification of AKT2 serine/threonine kinase gene (36,37), amplification of Rsf-1 chromatin remodeling gene (38), and inactivation of the p16 gene as a result of promoter methylation, mutation, or homozygous deletion of the p16 gene. These genetic changes are rare in borderline tumors and invasive low-grade serous carcinomas. As these molecular genetic studies were not carefully correlated with the morphological findings and were described simply as "serous carcinomas," they have been referred to as "presumably high-grade" because the vast majority of serous carcinomas are high grade. In addition to molecular genetic alterations, both low- and high-grade serous carcinomas are characterized by distinct gene expression profiles. For example, transcriptome-wide gene expression profiling has demonstrated that human leukocyte antigen (HLA)-G (39) and apolipoprotein E (apoE) (40) are overexpressed in most high-grade serous carcinomas, but rarely in low-grade serous carcinomas. HLA-G immunoreactivity, ranging from focal to diffuse, has been detected in 45 of 74 (61%) high-grade ovarian serous carcinomas, but in none of the 18 low-grade serous carcinomas or 26 serous borderline tumors (atypical proliferative tumors and noninvasive MPSCs) (39). A similar correlation of HLA-G expression with behavior has been observed in large cell carcinoma of the lung (41). A possible mechanism that explains the association of HLA-G expression with prognosis is that HLA-G appears to facilitate tumor cell evasion of the immune system by protecting malignant cells from lysis by natural killer cells (42).

The genes that are specifically expressed in other types of ovarian carcinomas remain largely unknown. Recently, hepatocyte nuclear factor-1a and glutathione peroxidase 3 have been reported as molecular markers for ovarian clear cell carcinoma as both genes are highly expressed in ovarian clear cell carcinomas, but rarely in other ovarian carcinomas (43,44). Chromosomal instability as evidenced by allelic imbalance has been studied in high- and low-grade serous carcinomas as well as their precursors (14). A progressive increase in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was noted when comparing atypical proliferative tumors with intraepithelial and invasive low-grade serous carcinomas. The allelic imbalance patterns in atypical proliferative tumors were also found in intraepithelial low-grade serous carcinomas containing adjacent atypical proliferative tumor components, further supporting the view that atypical proliferative tumors are the precursors of low-grade serous carcinomas. In contrast, all high-grade serous carcinomas including the very earliest tumors showed high levels of allelic imbalance. As allelic imbalance reflects chromosomal instability, the aforementined findings suggest a step-wise increase in chromosomal instability in the progression to low-grade serous carcinoma, in contrast to the high level of chromosomal instability in high-grade serous carcinoma, even in their earliest stage of development.

The stepwise progression of type I carcinomas closely simulates the "adenoma-carcinoma" sequence in colorectal cancer. In mucinous carcinoma for example, morphological transitions from cystadenoma to an atypical proliferative tumor, to intraepithelial carcinoma, and invasive carcinoma have been recognized for some time. Also, an increasing frequency of KRAS mutations at codons 12 and 13 has been described in cystadenomas, borderline tumors, and mucinous carcinomas, respectively (45-49). In addition, mucinous carcinoma, and the adjacent mucinous cystadenoma, and borderline tumor share the same KRAS mutation (45). Similarly, in endometrioid carcinomas, mutation of p-catenin has been reported in approximately one-third of cases (50,51), and mutations of KRAS can also be observed, albeit at a lesser frequency (nearly 10%) in most studies (11,19,49,52,53). On the other hand, mutation of the tumor suppressor, PTEN, occurs in 20% of endometrioid carcinomas, rising to 46% in these tumors with 10q23 loss of heterozygosity (54). Moreover, similar molecular genetic alterations including loss of heterozygosity at 10q23 and mutations in PTEN have been reported in endometriosis, atypical endometriosis, and ovarian endometrioid carcinoma in the same specimen (54-59). The molecular genetic findings together with the morphological data showing a frequent association of endometriosis with endo-metrioid adenofibromas and atypical proliferative (borderline) tumors, adjacent to invasive well-differentiated endometrioid carcinoma provide evidence of stepwise tumor progression in the development of endometrioid carcinoma. The importance of the genetic changes is highlighted by a recent report showing that inactivation of PTEN and activating mutation of KRAS are sufficient to induce the development of ovarian endometrioid carcinoma in a mouse model (60). Clear cell carcinoma is also frequently associated with endometriosis, clear cell adenofibromas, and atypical proliferative (borderline) clear cell tumors. But molecular evidence for the stepwise progression model is lacking because molecular markers specific to clear cell neoplasms have only recently been identified (43,44). Mutations in transforming growth factor-p receptor type II has been found in two of three clear cell carcinomas, but rarely in other histological types of ovarian carcinomas (61). Microsatellite instability is present in endometrioid and clear cell carcinoma, but is only rarely detected in serous and mucinous tumors (62,63). These findings provide further evidence of the close relationship of endometrioid and clear cell carcinoma and point to a common precursor lesion for these two neoplasms.

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