Mutation of BRAF and KRAS

Several unique molecular changes characterize low-grade and high-grade serous carcinomas (Table 2-4 and Fig. 2-4). Among them, the most significant molecular genetic alterations are mutations in BRAF and KRAS oncogenes. The RAS, RAF, MEK, ERK, and MAP cascade is important for the transmission of growth signals

Table 2-3. Summary of Clinicopathologic Features of the Prototypic Type I and Type II Tumors

Type I: Low-Grade Serous Carcinoma Type II: High-Grade Serous Carcinoma

Frequency

25% of serous carcinomas* Histologic Feature Micropapillary architecture Low-grade nuclei Low mitotic index Precursor Lesions Serous cystadenoma

Serous atypical proliferative (borderline) tumor Clinical Behavior

Indolent; slow progression 5-year survival 55%+

~75% of serous carcinomas*

Solid nests and masses High-grade nuclei High mitotic index

Not known

Probably from ovarian surface epithelium or inclusion cysts (de novo)

Aggressive; rapid progression; 5-year survival -30%+

Response to Chemotherapy

Poor Good, although recurrence Is common

*Based on a survey at the Johns Hopkins University Hospital. Most patients eventually die from the disease. 1Advanced-stage tumors.

Table 2-4. Summary of Molecular Features of Prototypic Type I and Type II Tumors

Type I: Low-Grade Type II: High-Grade

Serous Carcinoma Serous Carcinoma

Type I: Low-Grade Type II: High-Grade

Serous Carcinoma Serous Carcinoma

KRAS mutations

35%

0%

BRAF mutations

30%

0%

BRAF or KRAS mutations

65%

0%

TP53 mutations

0%

50-80%

HLA-G expression

0%

61 %

Proliferation (Ki-67) index

10-15%

(lgsca)

ERRB

Cadherin

(lgsca)

ERRB

LGSCA MCA

LGSCA MCA

ß-catenin EMCA

(lgsca) BRAF MEK

ß-catenin EMCA

(lgsca) BRAF MEK

mTOR

Cyclin E1 CLef/tcfS I

Cyclin D1

(hgsca)

p53 < —J (Cell growth + survival + proliferation

Figure 2-4. The main molecular genetic changes involved in different types of ovarian epithelial cancer. Several pathways have been known to be abnormal in ovarian cancer including p53, MAPK, cadherin/p-catenin, PI3CA/AKT, and cyclin E pathways. High-grade serous carcinoma (HGSCA) is characterized by very high frequency of mutations in p53, amplifications in cyclin E, AKT, and PI3CA loci. Low-grade serous carcinoma (LGSCA) harbor activating mutations in KRAS, BRAF, or ERRB2. Endometrioid carcinoma (EMCA) contains mutations in p-catenin and PTEN. Although the molecular genetic changes in clear cell carcinoma (CCCA) have not been extensively studied, mutations in PI3CA have been detected in approximately 20% of cases. Mucinous carcinoma (MCA) is characterized by mutations in KRAS in most cases.

into the nucleus.19 Oncogenic (activating) mutations in BRAF and KRAS result in constitutive activation of this pathway and contribute to neoplastic transformation. Recent studies have demonstrated that KRAS mutations at codons 12 and 13 occur in approximately one third of low-grade serous carcinomas (invasive MPSCs) and one third of borderline tumors (atypical proliferative tumor and noninvasive MPSC) but not in high-grade serous carcinomas.4,20 Similarly, BRAF mutations at codon 600 occur in 30% of low-grade serous carcinomas and 28% of borderline tumors but not in high-grade serous carcinomas.20 Mutations in BRAF and KRAS, therefore, were found in about two thirds of low-grade invasive serous carcinomas and atypical pro-liferative tumors and in noninvasive MPSCs, their putative precursors, but neither of the genes was mutated in high-grade serous carcinomas. It is interesting that BRAF mutations were found only in tumors with wild-type KRAS.20 The mutually exclusive nature of BRAF mutations and KRAS mutations in ovarian carcinoma is consistent with similar findings in melanoma and colorectal carcinoma21,22 and lends support for the view that BRAF and KRAS mutations may have an equivalent effect on tumorigenesis. Since mutations of BRAF and KRAS can be detected in small atypical proliferative serous tumors but not in serous cystadenomas,23 they seem to occur very early in the development of low-grade serous carcinoma. These data provide cogent evidence that the development of conventional high-grade serous carcinomas involves molecular mechanisms not related to mutations in BRAF and RAS.

Braf Und Kras

Figure 2-5. p53 signaling pathway. The p53 tumor suppressor is the most commonly mutated gene in human cancer. In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, various pathways lead to the dissociation of the p53 and mdm2 complex. The stable p53 protein is activated by phosphorylation, dephosphorylation, and acetylation, yielding a potent sequence-specific DNA-binding transcription factor. Once activated, p53 either induces a cell-cycle arrest to allow repair and survival of the cell or apoptosis to discard the damaged cell. The wide range of the biological effects of p53 can in part be explained by its activation of expression of a number of target genes including p21WAFI, GADD45, 14-3-3 sigma, bax, Fas/APO1, KILLER/DR5, PIG3, Tsp1, IGF-BP3, and others.

Figure 2-5. p53 signaling pathway. The p53 tumor suppressor is the most commonly mutated gene in human cancer. In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, various pathways lead to the dissociation of the p53 and mdm2 complex. The stable p53 protein is activated by phosphorylation, dephosphorylation, and acetylation, yielding a potent sequence-specific DNA-binding transcription factor. Once activated, p53 either induces a cell-cycle arrest to allow repair and survival of the cell or apoptosis to discard the damaged cell. The wide range of the biological effects of p53 can in part be explained by its activation of expression of a number of target genes including p21WAFI, GADD45, 14-3-3 sigma, bax, Fas/APO1, KILLER/DR5, PIG3, Tsp1, IGF-BP3, and others.

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