뇌종양에는 남녀 간에 위험의 차이가 있음을 알아냈다.

2019130: 국립암연구소 제공

연구원들은 수십 년 동안 남성이 여성보다 교아종이라는 공격적인 형태의 뇌종양에 걸릴 가능성이 높다는 것을 알고 있었다. 이 병의 표준요법에 대해 여성이 남성보다 더 잘 반응하는 경향이 있다는 증거도 있다.

이러한 성차이의 이유는 명확하지 않다. 그러나 새로운 연구는 교아종을 앓고 있는 여성과 남성이 치료에 다르게 반응하는 것으로 보이며 이러한 불균형의 원인이 될 수 있는 생물학적 요인을 밝혀내는 추가적인 증거를 제공한다.

이번 연구에서 세인트루이스 워싱턴 대학교 의과대학 연구진과 그 동료들은 MRI 결과와 종양 유전체 프로파일, 그리고 교아종 남녀의 생존자 정보를 분석했다.

이러한 데이터를 사용하여, 연구원들은 남성과 여성의 종양에서 서로 다른 분자 프로파일을 발견했고, 이러한 프로파일이 생존의 차이와 관련이 있다는 것을 보여주었다. 그 연구결과는 12일 병진 의과학회지에 실렸다.

"우리의 발견과 생물학에서 성별에 따른 특정한 차이들의 중요성에 대한 데이터의 증가는 우리가 정말로 연구가 성 차이를 감지하도록 적절하게 설계되었는지 확인할 필요가 있다는 것을 암시합니다,"라고 이 연구를 공동 이끈 워싱턴 대학의 조슈아 루빈 박사가 말했다.

루빈 박사는 "연구원들이 수십 년 동안 교아종과 다른 뇌종양 발생률에서 상당한 성별 차이를 알고 있었지만 대규모 분석을 실시하는 대부분의 연구자들은 남녀 환자들의 데이터를 계속 병합해 왔다"고 덧붙였다.

향후 교아종 연구에서 연구자들은 남성과 여성의 세포와 동물과 환자에 대해 병렬적이지만 별도의 분석을 실시해야 한다고 공동 연구자인 워싱턴 대학의 징친 "Rosy" 루오 박사는 말했다.

성별 차이의 생물학

일부 암을 포함한 많은 질병은 남성과 여성의 발병률이 다르거나 환자의 성별에 따라 다른 증상을 일으킨다. 이러한 차이점들은 종종 테스토스테론이나 에스트로겐과 같은 성호르몬과 연관되어 있는데, 이것은 남성과 여성 사이의 많은 생물학적 차이에 기여한다.

그러나 어린 시절을 포함한 모든 연령의 여성들보다 남성들이 악성 뇌종양에 걸릴 가능성이 더 높다. 이는 성호르몬 순환효과만으로 그 불균형을 설명할 수 없음을 시사한다.

루빈 박사는 "폐경 후 성인은 물론 어린 아이들과 젊은 성인의 암에서 성 차이를 보인다는 것은 성호르몬 순환이 그 차이에 대한 원인이 아니라는 의미"라고 설명했다.

성호르몬을 순환시켜 질병에 영향을 줄 때, 병행하는 성호르몬 수치의 빈도와 강도에 변화가 생긴다. 대부분의 암에서 성별 간 차이는 그렇지 않다."고 그가 말했다.

뇌종양 성장과 확산의 추적

루빈 박사는 현재 연구는 "우리는 남성과 여성, 그리고 소년과 소녀 사이의 교아종 발병률에서 큰 차이를 본다"는 임상적 관찰에서 비롯되었다. 남성들은 전반적으로 여성들보다 교아종(교모세포종)이 발생할 가능성이 60% 더 높다.

연구의 초반에, 연구진은 남성 40, 여성 23명 등 교아종 치료 성인 63명을 대상으로 MRI 촬영과 생존 데이터를 분석했다. 환자들은 수술을 받았고, 이어서 화학요법과 방사선요법을 받았다.

이 분석을 위해 마요 클리닉의 수리 종양학자인 크리스틴 스완슨 박사 등 연구진은 MRI 스캔과 컴퓨터 모델을 이용해 치료 중 종양의 성장과 확산을 평가했으며 이를 종양 증가 속도라고 부른다.

초기 종양 증가 속도는 남성과 여성 모두 비슷했지만, 여성만이 신경성 종양을 치료하는 데 흔히 사용되는 화학요법 약물인 테모졸로마이드(상표명 : 테모다)로 치료한 후 종양의 성장이 현저하게 감소했다는 것을 연구원들이 발견했다.

이 연구에 참여하지 않은 NCI 암 생물학과의 콘스탄틴 살니코우 박사(DCB)MRI 연구 결과 교아종 표준 치료가 남성보다 여성에 더 효과적이라는 것을 알 수 있었다고 말했다.

살니코우 박사는 "교아종의 발병률과 결과 차이의 징후에서 잘 정립된 성별 차이에도 불구하고, 분자 레벨에서 남성과 여성의 교아종을 구별하거나 이러한 생물학적 차이를 특정할 수는 거의 없다"고 말했다.

Glioblastoma Study Highlights Sex Differences in Brain Cancer

January 30, 2019, by NCI Staff

Researchers have known for decades that men are more likely than women to develop an aggressive form of brain cancer called glioblastoma. There is also evidence that women tend to respond better than men to standard therapy for this disease.

The reasons for these sex differences are not clear. But a new study provides further evidence that women and men with glioblastoma appear to respond differently to treatment and identifies biological factors that might contribute to this disparity.

In the study, researchers at Washington University School of Medicine in St. Louis and their colleagues analyzed MRI results, genomic profiles of tumors, and information about survival from men and women with glioblastoma.

Using these data, the researchers uncovered different molecular profiles in the tumors of men and women and showed that these profiles were associated with differences in survival. The results appeared in Science Translational Medicine on January 2.

“Our findings and the growing body of data on the importance of sex-specific differences in biology suggest that we really need to ensure that studies are appropriately designed to detect sex differences,” said Joshua Rubin, M.D., Ph.D., of Washington University, who co-led the study.

Although researchers have been aware of substantial sex differences in the incidence of glioblastoma and other brain tumors for decades, most researchers conducting large-scale analyses have continued to merge data from patients of both sexes, Dr. Rubin added.

In future work in glioblastoma, researchers should conduct parallel but separate analyses of male and female cells, animals, and patients, noted Jingqin “Rosy” Luo, Ph.D., of Washington University, who also co-led the study.

The Biology of Sex Differences

Many diseases, including some cancers, occur at different rates in males and females or cause different symptoms depending on the patient’s sex. These differences are frequently linked to sex hormones, such as testosterone or estrogen, which contribute to many biological differences between men and women.

But males are more likely to develop malignant brain tumors than females at all ages, including in childhood. This suggests that the disparity cannot be explained solely by the effects of circulating sex hormones.

“The fact that we see sex differences in cancers in young children and young adults, as well as post-menopausal adults, means that circulating sex hormones are not responsible for the differences,” said Dr. Rubin.

When circulating sex hormones affect a disease, there are changes in the frequency and severity of the disease that parallel sex hormone levels, he continued. “That is not the case for sex differences in most cancers.”

Tracking the Growth and Spread of Brain Tumors

The current study grew out of the clinical observation that “we see a big difference in the incidence of glioblastoma between men and women and between boys and girls,” said Dr. Rubin. Males are 60% more likely to develop glioblastoma overall than females.

In the first part of the study, the researchers analyzed MRI scans and survival data for 63 adults treated for glioblastoma, including 40 men and 23 women. The patients had received surgery, followed by chemotherapy and radiation therapy.

For this analysis, the researchers, including Kristin Swanson, Ph.D., a mathematical oncologist at the Mayo Clinic, used the MRI scans and computational models to assess the growth and spread of tumors during treatment, a combined measure called tumor growth velocity.

Initial tumor growth velocities were similar for both women and men, but only women experienced a significant decline in tumor growth after treatment with the chemotherapy drug temozolomide (Temodar), which is commonly used to treat glioblastoma, the researchers found.

“The MRI studies indicated that the standard treatment for glioblastoma is more effective for females than for males,” said Konstantin Salnikow, Ph.D., of NCI’s Division of Cancer Biology (DCB), who was not involved in the study.

“Despite well-established sex differences in the incidence [of glioblastoma] and emerging indications of differences in outcomes, there are few insights that distinguish male and female glioblastomas at the molecular level or that allow specific targeting of these biological differences,” Dr. Salnikow continued.

Profiling Glioblastoma Tumors from Men and Women

To explore the molecular basis of this sex difference in treatment response, the researchers analyzed gene expression data from glioblastoma tumors included in The Cancer Genome Atlas (TCGA).

Most genes were expressed similarly in the glioblastoma tumors of men and women. But by focusing on genes that were expressed differently, the researchers found that they could separate patients with glioblastoma into five male and five female groups, or clusters. They validated the clusters by analyzing several independent data sets.

An analysis of the differentially expressed genes in the clusters showed that “survival in males was most significantly determined by genes that regulate cell division,” Dr. Rubin said. For survival in females, the most important pathway involved the expression of genes called integrins, which, he added, are involved in the spread of tumors.

Among women in the study, those whose tumors had low expression of integrin-signaling components lived, on average, slightly over 3 years after diagnosis, compared with just over a year for women whose tumors had other molecular profiles.

For men, those whose tumors had low expression of cell-cycle signaling components survived more than 18 months, on average, whereas the other tumor profiles were associated with survival of just over a year.

To explore the clinical relevance of these genetic signatures, the researchers carried out laboratory experiments in which they exposed a panel of glioblastoma cell lines from a series of male and female patients to four types of chemotherapy.

This analysis also showed associations between the cell-cycle signature and longer survival in men and between the integrin signature and longer survival in women.

Focusing on Mutations in the IDH1 Gene

The researchers also analyzed a gene called IDH1, which, when mutated, is thought to be an important driver of glioblastoma.

In previous studies, IDH1 mutations have been associated with better outcomes in glioblastoma. But in the current study, women with IDH1-mutant tumors were all in the cluster with the best survival, whereas in men, IDH1-mutant tumors were distributed in all the clusters.

“This was a very interesting result of our study,” said Dr. Rubin. “The longest-surviving female cluster was aligned with current thinking that IDH1 mutations are associated with better survival in glioblastoma. But in males that was not true.”

The finding suggests that there may be a sex-specific effect of IDH1 mutations on survival in glioblastoma, he added.

Raising Awareness about Sex Differences

“Sex differences in cancer are an understudied area of research, and more of these studies are needed to make progress in what is often known as precision, or personalized, medicine,” said Dr. Salnikow, noting that the results of the current study need to be replicated by larger studies.

Researchers can learn a lot about cancer by identifying the molecular changes driving the disease, said DCB's Nastaran Zahir, Ph.D., who was not involved in the research.

“Looking at these molecular changes in the context of sex differences and using computational modeling approaches could enhance our ability to predict which patients are likely, for instance, to respond to treatment or to experience disease progression,” Dr. Zahir added.

Dr. Rubin cautioned that more research on sex differences in glioblastoma is needed before doctors can incorporate the approach into the clinic. He is hopeful that the current study will raise awareness about the need to pursue this area of research.

“No matter which aspect of glioblastoma we looked at, we could see sex-specific differences,” said Dr. Rubin. “As we learn more, you could imagine that treatment for glioblastoma might need to be delivered in a sex-specific manner in the future.”

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