Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary

• Published in: Modern pathology Vol. 33; no. 8; pp. 1606 - 1617
• Main Authors: Da Cruz Paula, Arnaud, da Silva, Edaise M., Segura, Sheila E., Pareja, Fresia, Bi, Rui, Selenica, Pier, Kim, Sarah H., Ferrando, Lorenzo, Vahdatinia, Mahsa, Soslow, Robert A., Vidal, August, Gatius, Sonia, Przybycin, Christopher G., Abu-Rustum, Nadeem R., Matias-Guiu, Xavier, Rubin, Brian P., Reis-Filho, Jorge S., DeLair, Deborah F., Weigelt, Britta
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2020; Elsevier Limited
• Subjects: 45/23; 45/77; 631/67/1517/1709; 631/67/69; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Cell cycle; Female; Gene Expression Profiling; Genes, cdc - genetics; Genomes; Granulosa Cell Tumor - genetics; Humans; Laboratory Medicine; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Mutation; Mutation hot spots; Ovarian cancer; p53 Protein; Pathology; Sequence analysis; Telomerase - genetics; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-020-0514-3

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent
FOXL2
c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (
n
 = 7), primary aGCTs that subsequently recurred (
n
 = 9) and their matched recurrences (
n
 = 9), and aGCT recurrences without matched primary tumors (
n
 = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to
FOXL2
and
TERT
promoter Sanger sequencing analysis. All aGCTs harbored the
FOXL2
C134W hotspot mutation.
TERT
promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%,
p
 = 0.017). In addition, mutations affecting
TP53
,
MED12
, and
TET2
were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that
TERT
promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including
TERT
,
MED12
, and
TP53
mutations and
CDKN2A/B
homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that
TERT
promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.