Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 14;28(20):4456-4465.
doi: 10.1158/1078-0432.CCR-21-4183.

MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma

Beryl Manning-Geist #  1 , Sushmita Gordhandas #  1 , Ying L Liu  2   3   4 , Qin Zhou  5 , Alexia Iasonos  5 , Arnaud Da Cruz Paula  1 , Diana Mandelker  6 , Kara Long Roche  1   7 , Oliver Zivanovic  1   7 , Anna Maio  8 , Yelena Kemel  9 , Dennis S Chi  1   7 , Roisin E O'Cearbhaill  2   3 , Carol Aghajanian  2   3 , Britta Weigelt  10 , M Herman Chui #  10 , Rachel N Grisham #  2   3
Affiliations

MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma

Beryl Manning-Geist et al. Clin Cancer Res. .

Abstract

Purpose: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC).

Experimental design: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected.

Results: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation.

Conclusions: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: Outside the submitted work, B Weigelt reports ad hoc membership of the scientific advisory board of Repare Therapeutics; YL Liu reports research funding from GSK and AstraZeneca; MH Chui reports an honorarium from Roche and research funding from PaigeAI; RE O’Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, and Curio; R Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. DS Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE.

Figures

Figure 1.
Figure 1.. Consort diagram representing selection of the low-grade serous carcinoma (LGSC) cohort.
MSK-IMPACT (Memorial Sloan Kettering Cancer Center – Integrated Mutation Profiling of Actionable Cancer Targets) was queried for all ovarian carcinomas that had undergone molecular analysis. All non-LGSCs were excluded (n=1,881). Pathology reports for the remaining 182 cases were manually reviewed. Duplicates and cases with high-grade or non-invasive histology were excluded (n=58). The remaining 124 cases underwent central pathology review of tumor diagnostic slides, resulting in a final cohort of 119 LGSCs.
Figure 2.
Figure 2.. Histomorphology of low-grade serous carcinoma.
A) A typical case characterized by small nests of monotonous tumor cells infiltrating through fibrotic stroma, and occasional psammomatous calcifications. B) Another case exhibiting the less common inverted macropapillary invasion pattern. C) Invasive low-grade serous carcinoma in the peritoneum, previously termed “invasive implant”, associated with ovarian serous borderline tumor (inset). D-F) Representative excluded cases after central pathology review. D) Tumor with low cellularity precluding histologic subtyping and reliable molecular analysis. E) High-grade serous carcinoma exhibiting marked nuclear pleomorphism and high mitotic activity. F) Seromucinous carcinoma, characterized by mucin-producing glands, and considered to be a variant of endometrioid carcinoma.
Figure 3.
Figure 3.. Overall survival of patients with MAPK pathway–driven low-grade serous carcinomas (n=71, harboring somatic genetic alterations in BRAF KRAS, NRAS, and others) compared with those lacking MAPK pathway alterations (n=48).
Figure 4.
Figure 4.. Somatic mutational landscape for the full cohort of low-grade serous ovarian carcinomas (LGSCs) (n=119).
A) Percentage of mutated samples are presented on the right. Heatmap comparisons of mutations within clinical groups: age at diagnosis ≤50 years vs. >50 years (B), and platinum-sensitive vs. platinum-resistant disease (C). *Statistically significant associations
See this image and copyright information in PMC

Comment in

References

    1. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv259. - PubMed
    1. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010;34(3):433–43. - PMC - PubMed
    1. Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004;28(4):496–504. - PubMed
    1. Kurman RJ, Shih Ie M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm. Hum Pathol 2011;42(7):918–31. - PMC - PubMed
    1. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol 2010;221(1):49–56. - PMC - PubMed

Publication types

Substances