Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients.
Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients.
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DOI：
10.1002/gcc.22515
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Ried T
中科院分区：
文献类型：
--
作者：
Oltmann J;Heselmeyer-Haddad K;Hernandez LS;Meyer R;Torres I;Hu Y;Doberstein N;Killian JK;Petersen D;Zhu YJ;Edelman DC;Meltzer PS;Schwartz R;Gertz EM;Schäffer AA;Auer G;Habermann JK;Ried T
乳腺癌的临床病程因患者而异。目前，治疗的选择依赖于临床参数以及组织学和分子肿瘤特征。遗憾的是，这些标记物仅对一小部分患者提供信息。因此，疾病结果的额外预测因素对于治疗分层很有价值。大量研究表明，核DNA含量的变异程度，即非整倍性决定预后。我们的目的是进一步阐明非整倍性的分子基础。我们分析了 5 个二倍体肿瘤和 6 个非整倍体肿瘤，并进行了 20 多年的随访。通过使用由 10 个探针组成的多重探针组进行 FISH 来计算单个细胞中的拷贝数，并通过对 563 个癌症相关基因进行测序，我们分析了非整倍性如何与肿瘤内异质性相关。在我们的队列中，没有一位二倍体肿瘤患者在随访期间死于乳腺癌，而六名非整倍体肿瘤患者中有四人死于乳腺癌（平均生存期为 86.4 个月）。 FISH 分析显示非整倍体肿瘤的基因组不稳定性和瘤内异质性显着增加。仅在 20% 的二倍体癌症中观察到 MYC 增加，而所有非整倍体病例均显示出增加。二倍体和非整倍体肿瘤中的突变负担相似，然而，在二倍体肿瘤中未观察到 TP53 突变，但在我们集体的所有非整倍体肿瘤中观察到 TP53 突变。我们得出的结论是，通过多重 FISH 定量测量肿瘤内异质性、检测 MYC 扩增和 TP53 突变可以增强乳腺癌患者的预后。
The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective. We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients.
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影响因子：
6
作者：
Heselmeyer-Haddad, Kerstin;Garcia, Lissa Y. Berroa;Ried, Thomas
通讯作者：
Ried, Thomas
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
7.4
作者：
Bettaieb A;Paul C;Plenchette S;Shan J;Chouchane L;Ghiringhelli F
通讯作者：
Ghiringhelli F
DOI：
10.1002/cyto.990080217
发表时间：
1987-03-01
期刊：
CYTOMETRY
影响因子：
--
作者：
CORNELISSE, CJ;VANDEVELDE, CJH;HERMANS, J
通讯作者：
HERMANS, J
影响因子：
4.3
作者：
Duesberg, Peter;Mandrioli, Daniele;Nicholson, Joshua M.
通讯作者：
Nicholson, Joshua M.