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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

ABSTRACT: Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C?>?T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C?>?T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C?>?T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09-2.52, p?=?0.018), with a more pronounced survival effect among familial cases (HR?=?2.93, 95% CI 1.5-5.76, p?=?1.80 × 10^-3 ). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR?=?1.8, 95% CI 1.09-2.98, p?=?0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR?=?3.43, 95% CI 1.6-7.34, p?=?1.50?×?10^-3 ) but not among radiotherapy treated patients (HR?=?1.35, 95% CI 0.82-2.23, p?=?0.237). Significant interaction was found between the mutation and radiotherapy (p?=?0.040). Immunohistochemical analyses show that c.5101C?>?T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C?>?T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.

SUBMITTER: Kiiski JI

PROVIDER: S-EPMC5095781 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

Kiiski Johanna I JI Fagerholm Rainer R Tervasmäki Anna A Pelttari Liisa M LM Khan Sofia S Jamshidi Maral M Mantere Tuomo T Pylkäs Katri K Bartek Jiri J Bartkova Jirina J Mannermaa Arto A Tengström Maria M Kosma Veli-Matti VM Winqvist Robert R Kallioniemi Anne A Aittomäki Kristiina K Blomqvist Carl C Nevanlinna Heli H

International journal of cancer 20160919 12

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 1 ...[more]

PMID: 27542569

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Project description:BackgroundER+HER2+ breast cancer requires most types of systemic therapies perioperatively. However, treatment resistance is often experienced. The current study investigated the predictive and prognostic value of intratumoral heterogeneity and conventional clinicopathological factors in patients with ER+HER2+ breast cancer.MethodsThis research included two patient cohorts with ER+HER2+ breast cancer. Cohort A included patients who underwent surgery without neoadjuvant chemotherapy (NAC). Cohort B comprised patients who received NAC followed by surgery. Intratumoral heterogeneity was assessed via ER and HER2 double staining, and the number of cells stained with different patterns of ER and HER2 was counted.ResultsIn total, 11 of 92 tumors in cohort A and four of 45 tumors in cohort B consisted exclusively of double-positive (ER+ and HER2+) cells (homogeneous). The rest had different combinations of cells (heterogeneous). The pathological complete response (pCR) rates differed based on tumoral cell components but not intratumoral heterogeneity. The pCR rate of tumors with ER-HER2+ cells but without HER2- cells was higher than that of others (45.5% vs 4.3%; p = 0.0013). Low ER and PgR Allred scores indicated better pCR rates than high scores (p = 0.0005 and 0.024, respectively). Multivariate analysis showed that the ER Allred score and cell component of ER-HER2+ cells without HER2- cells were independent predictors of pCR (p = 0.0055 and 0.0081, respectively). In cohort B, posttreatment Ki67, but not pCR, was a prognostic factor of DFS and OS (p = 0.028 and 0.017, respectively). The prognostic value of combined posttreatment Ki67 and pCR was superior to that of either alone. Combined pCR and posttreatment Ki67 had an independent prognostic value for DFS and OS (p = 0.0068 and 0.0101, respectively).ConclusionsIn ER+HER2+ breast cancer, the presence of ER-HER2+ cells without HER2- cells was independently associated with pCR. Combined posttreatment Ki67 and pCR can be more precise in predicting prognosis than pCR alone.

Project description:Rationale: Epigenetic mechanisms are fundamental processes that can modulate gene expression, allowing cellular adaptation to environmental conditions. Hypoxia is an important factor known to initiate the metastatic cascade in cancer, activating cell motility and invasion by silencing cell adhesion genes. G9a is a histone methyltransferase previously shown to accumulate in hypoxic conditions. While its oncogenic activity has been previously reported, not much is known about the role G9a plays in the hypoxia-mediated metastatic cascade. Methods: The role of G9a in cell motility in hypoxic condition was determined by inhibiting G9a either by short-hairpin mediated knock down or pharmacologically using a small molecule inhibitor. Through gene expression profiling, we identified CDH10 to be an important G9a target that regulates breast cancer cell motility. Lung metastasis assay in mice was used to determine the physiological significance of G9a. Results: We demonstrate that, while hypoxia enhances breast cancer migratory capacity, blocking G9a severely reduces cellular motility under both normoxic and hypoxic conditions and prevents the hypoxia-mediated induction of cellular movement. Moreover, inhibition of G9a histone methyltransferase activity in mice using a specific small molecule inhibitor significantly reduced growth and colonisation of breast cancer cells in the lung. We identify the type-II cadherin CDH10 as being a novel hypoxia-dependent gene, directly repressed by G9a through histone methylation. CDH10 overexpression significantly reduces cellular movements in breast cancer cell lines and prevents the hypoxia-mediated increase in cell motility. In addition, we show that CDH10 expression is prognostic in breast cancer and that it is inversely correlated to EHMT2 (G9a) transcript levels in many tumor-types, including breast cancer. Conclusion: We propose that G9a promotes cellular motility during hypoxic stress through the silencing of the cell adhesion molecule CDH10 and we describe CDH10 as a novel prognostic biomarker for breast cancer.

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

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