Summary #

Introduction #

TNBC는 non-TNBC에 비해 chemotherapy가 더 잘 듣는다. 일반적으로 좀 더 proliferative하기 때문임. 반면 잦은 재발로 poor survival 하다.

Only 31% of TNBC patients experience pathological complete responses after chemotherapy, emphasizing the need for targeted therapies.

몇몇의 gene signature가 개발되어 치료 결과를 예측하는데 사용된다.

1. MammaPrint
2. OncotypeDx
3. Theros

이들은 tumor response나 survival time과 같은 clinical phenotype에 기반함 -- core biological mechanism을 확인하지 못함

gene coexpression signature에 기반한 attractor metagenes

1. Chromosome instability (CIN)
2. Mesenchymal transtion (EMT)
3. lymphocyte-specific immune recruitment

매우 정확한 breast cancer survival 예측을 가능하게 함.

본 연구는 Oncomine DB를 이용하여, TNBC, non-TNBC에서 commonly deregulated되어 subgroup을 aggressive하게 하는 차이를 비교함 -- CIN, ER 관련 206개의 유전자 확인

TTK inhibition이 survival과 관련있음

Mitosis-independent expression of TTK protein was prognostic in TNBC and other aggressive breast cancer subgroups, suggesting that protection of CIN/aneuploidy drives aggressiveness and treatment resistance.

Results #

Meta-analysis of Gene expression profiles in TNBC #

Oncomine의 8개 dataset에서 492 TNBC와 1382 non-TNBC를 비교함 - overexpressed 1600, underexpressed 1580 유전자 확인

또한, metastases 512 환자와 non-metastases 732 환자를 구분하는 overexpressed 500, underexpressed 480 유전자 확인

마지막으로, 5년내 사망한 232 환자와 생존환자 879 명을 구분하는 overexpressed 500, underexpressed 500 유전자 확인

이들 분석을 종합하여, TNBC에서 metastasized 이거나, 5년내 사망한 overexpressed 305, underexpressed 341 유전자 확인 -- METABRIC 데이터로 validation하여 overexpressed 117, underexpressed 89 총 206개의 유전자가 TNBC (n=250)에서 adjacent tissue (n=144) 대비 deregulated 라고 확인

Clinico-pathological features of the aggressiveness gene list #

이 206개 유전자를 aggressiveness gene list라고 명명.

• over 117 중 45개가 CIN metagene
• under 89 중 19개가 ER metagene

Figure 1a는 TNBC에서 CIN up, ER downregulation.

aggressive score = CIN / ER

이 점수로 METABRIC Survival analysis하니, TNBC가 아닌 경우에도 의미있게 나옴.

One network of direct interactions in the aggressiveness gene list associates with patient survival #

IPA 이용하여 Biological network 분석

다음 기준으로 추가로 유전자 선택

1. CIN, ER 관련
2. overall survival과 상관도 높음
3. high/row agressiveness score 환자들에게서 2배 이상 차이나는 것들

이를 통해,

• 2 ER metagene: MAPK, MYB
• 6 CIN metagene: MELK, MCM10, CENPA, EXO1, TTK, KIF2C

The 8-gene aggressiveness score in multivariate survival analysis #

GSE2990, GSE3494, GSE203465, GSE25066에서 함께 확인

Therapeutic targets in the aggressiveness gene list #

overexpressed CIN metagenes are involved in,

• Mitosis
• Spindle assembly
• checkpoint
• Kinetochore attachment
• chromosome segregation
• mitotic exit

So, targets for CDK1, AURKA/AURKB were clinically tried.

siRNA depection against 25 CIN metagenses in 3 TNBC cell lines: MDA-MB-231, SUM159PT and Hs578T --> 4 genes (TTK, TPX2, NDC80 and PBK) consistently affected the survival.

TTK showed worst survival.

TTK expression in aggressive tumors and potential for combination therapy #

High TTK mRNA expression was associated with

• younger age of diagnosis
• large tumor size
• high tumor grade
• higher Ki67 expression
• TP53 mutation
• ER/PR-negative tumor phenotype, HER2 positivity and TNBC

Discussion #

More recently, a minimal gene set that captures the CIN signature CIN4 (AURKA, FOXM1, TOP2A and TPX2) was described as the first clinically applicable quantitative PCR-derived measure of tumor aneuploidy

Materials and methods #

Meta-analysis of global gene expression in TNBC #

Ingenuity Pathway Analysis and derivation of the eight-gene list #

Cell culture and drug treatments #

Breast cancer tissue microarrays, immunohistochemical and survival analysis #

Other statistical analysis #

Incoming Links #

Related Articles (Article 0) #

• Triple-negative breast cancer

Suggested Pages #

• 0.100 Triple-negative breast cancer: an unmet medical need
• 0.025 Cochrane Library
• 0.025 PubMed
• 0.025 May 1
• 0.025 청년의사
• 0.025 October 24
• 0.025 bioRxiv
• 0.025 Enhancer
• 0.025 Funnel plot
• 0.025 PCGF2
• More suggestions...