TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high‐grade serous carcinoma—evidence supporting the clonal relationship of the two lesions

Abstract

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and ‘primary peritoneal’ (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations.

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

“…An important feature of HGSOC, which may facilitate early detection by high-sensitivity sequencing, is the high prevalence of tumor protein p53 gene (TP53) mutations (>96%) (15,16), even in premalignant lesions (17). Moreover, >95% of TP53 mutations cluster in exons 4-10 (15), which provides a relatively small target to perform cost-efficient ultra-deep sequencing (8).…”

Use of cervical mucus to screen for gynecological malignancies: a pilot study

“…In addition, SSCP detected potential precancerous lesions in the fallopian tube which suggests that it might detect very early events in fallopian tube and ovarian cancer development. [8][9][10] We could not include cases of high-grade carcinomas of the ovary as the cases we received within our inclusion period had involvement of the serosal surface. The only ovarian cancer we could include was a stage 1 clear cell carcinoma that was negative for p53 immunostain, and had no identifiable TP53 mutation pattern by SSCP.…”

“…[1][2][3][4] These tumors can arise from different locations including peritoneum, ovaries, fallopian tubes and endometrium, and show molecular aberrations with TP53 gene mutation being the most common and one of the earliest events in their carcinogenesis. [5][6][7][8] High-grade epithelial ovarian cancers are highly aggressive tumors that represent 75% of all ovarian carcinomas, and account for 90% of deaths. They display high chromosomal instability and show TP53 mutations in 495% of cases.…”

“…They are also associated with TP53 mutations in about 50% of the cases. [6][7][8][9][10] Highgrade endometrial carcinomas also harbor TP53 mutations and have the worst prognosis among endometrial carcinomas. 5 All high-grade gynecological malignancies share the tendency to become symptomatic only at advanced stages, especially the ovarian high-grade carcinomas.…”

Ovarian carcinoma: An overview of current status

“…The maximum frequency (approximately 85%) of ovarian carcinoma is found within the epithelial cells [12] . Serous tubal intraepithelial carcinoma is a relatively recent finding in understanding the development of ovarian carcinoma and it represents the precursor lesion in high-grade serous ovarian carcinoma [13] . Figure 1.…”