Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li–Fraumeni syndrome)

Abstract Background The RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan. Methods Comprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines. Results One novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls. Conclusions Our data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.

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Abstract P5-09-08: Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients

10.1158/1538-7445.sabcs18-p5-09-08 ◽

2019 ◽

Author(s):

KJ Vogel Postula ◽

AK McGill ◽

E Sutcliffe ◽

PD Murphy ◽

RT Klein ◽

...

Keyword(s):

Breast Cancer ◽

Homologous Recombination ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Germline Variants

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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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