sábado, 7 de diciembre de 2019

Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular su... - PubMed - NCBI

2019 Nov 27. pii: S0090-8258(19)31664-6. doi: 10.1016/j.ygyno.2019.11.013. [Epub ahead of print]

Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtype and change in treatment course.

Takaya H1, Nakai H2, Sakai K3, Nishio K4, Murakami K5, Mandai M6, Matsumura N7.

Author information

1: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: htakaya@med.kindai.ac.jp.
2: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: nakai@med.kindai.ac.jp.
3: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: kasakai@med.kindai.ac.jp.
4: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: knishio@med.kindai.ac.jp.
5: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: kmurakami@med.kindai.ac.jp.
6: Department of Gynecology and Obstetrics, Kyoto University Graduateschool of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: mandai@kuhp.kyoto-u.ac.jp.
7: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: noriomi@med.kindai.ac.jp.

Abstract

OBJECTIVE:

High-grade serous ovarian cancers (HGSOC) are genomically characterized by homologous recombination deficiency (HRD) and TP53 mutations, which lead to intratumor heterogeneity (ITH). This study aimed to reveal the relationship between HRD, ITH and prognosis and analyze their changes during treatment.

METHODS:

We obtained 573 SNP array and gene expression array data from The Cancer Genome Atlas. SNP array data were processed to calculate the Clonality Index (CI) and loss of heterozygosity (LOH) scores. Gene expression array data were used for classifying molecular subtypes. Additionally, we obtained 33 samples from 20 HGSOC patients, including 4 samples from interval debulking surgery (IDS) and 9 samples from recurrent surgery.

RESULTS:

We divided HGSOC samples into 2 groups. The high CI group showed a high recurrent risk, and the high LOH group showed a statistically good prognosis. Combining the two factors, the high LOH/low CI group showed a statistically good prognosis. In terms of molecular subtypes, the mesenchymal subtype, which had a poor prognosis, showed a high CI with statisitically significant difference and the immunoreactive subtype, which had a good prognosis, showed a tendency to have a high LOH score. Throughout treatment, the CI decreased to one at the IDS (n = 4) and then increased at recurrence (n = 3). LOH scores greatly decreased in two cases at the IDS.

CONCLUSIONS:

ITH and HRD were associated with prognosis in HGSOC. ITH decreased after neoadjuvant chemotherapy, suggesting that the chemo-resistant cancer clone remains after chemotherapy.