Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Cross-resistance to molecules used in endocrine therapy is among the main challenges in the treatment of estrogen receptor-α (ERα) positive breast cancer. In this study, we used two different cell models of resistance to anti-estrogens: MVLN/CL6.7 cells and VP229/VP267 cells selected after exposure to tamoxifen respectively in vitro and in vivo to characterize a phenotype rarely observed, i.e. acquisition of cross-resistance to the pure ER antagonist fulvestrant. As MVLN/CL6.7 cells and VP229/VP267 cell lines are original and valuable models of cross-resistance to tamoxifen and fulvestrant, we examined candidate genes using a RTQ-PCR strategy to identify new biomarkers of endocrine resistance. Out of the 26 candidate genes tested, 19 displayed deregulation of expression at the basal level in at least one of the two resistant cell lines. Eight genes (TACC1, NOV, PTTG1, MAD2L1, BAK1, TGFB2, BIRC5, and CCNE2) were significantly overexpressed in samples from ER-positive breast cancer patients who relapsed after tamoxifen treatment (n=24) compared with samples from patients who did not (n=24). Five genes (TACC1, NOV, PTTG1, BAK1, and TGFB2) were correlated with significantly shorter relapse-free survival (univariate analysis). Finally, we identified TACC1 and a three-gene expression signature (TACC1, NOV, and PTTG1) as independent prognostic markers (multivariate analysis). Aberrant mRNA and protein levels of TACC1, NOV, and PTTG1 were also observed under tamoxifen and/or fulvestrant exposure in resistant CL6.7 cells compared with their respective control MVLN cells. In conclusion, our data identify TACC1, NOV, and PTTG1 as promising new markers that could be used in the clinical management of ER-positive breast cancer patients.

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Survival in women with breast cancer having children with pediatric tumors—-A nationwide cancer register study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.20071 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 20071-20071

Author(s):

H. Olsson ◽

A. Bladström

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Census Data ◽

Breast Cancer Diagnosis ◽

Population Based ◽

Breast Cancer Patients ◽

Genetic Syndromes ◽

Li Fraumeni Syndrome ◽

Pediatric Sarcomas ◽

Hereditary Factors

20071 Background: Breast cancer is a heterogenous disease with a minoruty of cases having a hereditary background. Hereditary factors could affect disease prognosis and it has been postulated that breast cancer patients having p53 germline mutations have an especially bad prognosis. In the present study survival has been compared in women with breast cancer with and without having a child with a pediatric tumour. Methods: Using and linking the population based fertility registry and cancer registry the offspring of all women with breast cancer diagnosed between 1961–1999 was traced in Sweden. All women with breast cancer with a pregnancy were included. Further all childhood cancer cases < 21 years of age were identified among the offspring. Likewise using census data the women’s overall survival was followed. Results: Patients with breast cancer having a child with a childhood malignancy (n = 254) had a significant worse survival compared with other women with breast cancer (n = 74,781), RR = 1.25, 95% CI 1.02–1.55, p < 0.04, adjusted for age at diagnosis, year of diagnosis, parity and time since last pregnancy. Mothers with children with pediatric sarcomas or acute myeloid leukemias seemed to be strongest associated with a worse survival in the mother (RR = 1.38 and RR = 1.69). The worse survival of the mother was present regardless if the breast cancer diagnosis was before or after 50 years of age. Conclusion: The results suggest that genetic syndromes such as the Li-Fraumeni syndrome and possibly other childhood/adult cancer syndromes if present worsens the survival for breast cancer patients. This familial factor may be of importance for future treatment stratification. It is unknown whether other tumor diseases in the mother may be associated with a worse survival if their children have had cancer. No significant financial relationships to disclose.

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Superior survival of breast cancer BRCA1 /2 mutation carriers harboringG/G at the -309 position at the MDM2 promoter compared to those harboring T/T or G/T at this SNP

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10600 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10600-10600

Author(s):

H. Nechushtan ◽

T. Hamburger ◽

S. Mendelson ◽

L. Kadouri ◽

N. Sharon ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Germ Line ◽

Age Of Onset ◽

Disease Onset ◽

Rank Test ◽

Breast Cancer Patients ◽

Mdm2 Snp309 ◽

Li Fraumeni Syndrome ◽

Mutation Carriers

10600 Background: A germ line single polymorphism in the promoter of the gene encoding the important modulator of P53, MDM2 has been described. The findings of G/G nucleotides at this position in contrast to G/Tor T/T were demonstrated to increase MDM2 transcriptional levels and were correlated with younger onset of cancers in patients with the Li-Fraumeni syndrome. Furhtermore gastric cancer patients harboring T/T at this position and treated with chemotherapy were found to have decresed survival compared to the other SNP carriers. P53 mutations appear in high frequency in tumors associated with BRCA1/2 mutations. Indeed it has been suggested that mutations in the p53 gene are a necessary step in tumorigenesis in BRCA tumors. Methods: Here we investigate the effect of the MDM2 SNP309 on overall survival and age of onset in breast cancer patients. MDM2 SNP309 was evaluated in Breast cancer Ashkenazy patients analyzed for the three common mutations in BRCA1/2- 180 patients who are positive for either of these mutation and 272 negative ones. 194 negative, Disease onset age and survival were analyzed for the different subgroups Results: Around a quarter of the whole population analyzed were identified as carriers of G/G at the -309 MDM2. There was no correlation between age of disease onset in either BRCA1/2mutation carriers and the specific genotype. In the BRCA1/2 mutation carriers we found a survival advantage in patients harboring the SNP309 G/G genotype(p-0.001 log rank test). Such an effect was not demonstrated in patients tested negative for the known Ashkenazy mutations Conclusions: In specific subgroups of breast cancer patients SNP309 G/G is associated with improved patient survival. A possible explanation for this finding could be the presence of a P53 which can be reactivated in the MDM2 SNP309 G/G carriers. No significant financial relationships to disclose.

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Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

Breast Cancer Research ◽

10.1186/s13058-019-1193-1 ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 14

Author(s):

Felipe Batalini ◽

Ellie G. Peacock ◽

Lindsey Stobie ◽

Alison Robertson ◽

Judy Garber ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cancer Susceptibility ◽

Somatic Mosaicism ◽

Susceptibility Genes ◽

Breast Cancer Patients ◽

Li Fraumeni Syndrome ◽

Clonal Hematopoiesis ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes

Abstract The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management. The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment. Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives. We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.

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