scholarly journals In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur Near Herpes Tumor Virus Sequences

2021 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Breast Cancer ◽  
Viral Infections ◽  
Sequence Data ◽  
Brca Mutation ◽  
Fragile Sites ◽  
Chromosome 2 ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Barr Virus ◽  
Chromosome Breaks

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, chromosome fragments may not be restored correctly. Resulting chromosome rearrangements can become critical breast cancer drivers. Because I had data from thousands of cancer structural alterations that matched viral infections, I wondered whether infections contribute to chromosome breaks and rearrangements in hereditary breast cancers. There are currently no interventions to prevent chromosome breaks because they are thought to be unavoidable. However, if chromosome breaks come from infections, they can be treated or prevented. I used bioinformatic analyses to test publicly available breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had the strongest matches to Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Many breakpoints were near sites that anchor EBV genomes, human EBV tumor-like sequences, EBV-associated epigenetic marks, and fragile sites. On chromosome 2, sequences near EBV genome anchor sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences. Five EBV genome anchor sites were near breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Breakpoint flanking regions resembled known EBV-cancers. Twenty-five breakpoints in breast cancers were within 1.25% of EBV cancer breakpoints. In addition to BRCA1 or BRCA2 mutations, all the breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can activate and produce nucleases that break chromosomes. Alternatively, anchored viral episomes can obstruct break repairs, whatever the cause. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

scholarly journals In BRCA1 and BRCA2 breast cancers, chromosome breaks occur near herpes tumor virus sequences

2021 ◽  
Author(s):  
Bernard A Friedenson
Keyword(s):  
Breast Cancer ◽  
Viral Infections ◽  
Brca Mutation ◽  
Chromosome 2 ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Barr Virus ◽  
Chromosome Breaks ◽  
Treatment And Prevention ◽  
Chromosomal Breakpoints

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosome fragments get lost or reattach indiscriminately. These mistakes are characteristic of hereditary breast cancer. We tested the hypothesis that mistakes in reattaching broken chromosomes preferentially occur near viral sequences on human chromosomes. We tested millions of DNA bases around breast cancer breakpoints for similarities to all known viral DNA. DNA around breakpoints often closely matched the Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Almost all breakpoints were near EBV anchor sites, EBV tumor variant homologies, and EBV-associated regulatory marks. On chromosome 2, EBV binding sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV variant sequences. Five viral anchor sites at critical genes were near breast cancer breakpoints. Twenty-five breast cancer breakpoints were within 1.25% of breakpoints in model EBV cancers. EBV-like sequence patterns around breast cancer breakpoints resemble gene fusion breakpoints in model EBV cancers. All BRCA1 and BRCA2 breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can attach and produce nucleases that break chromosomes. Alternatively, anchored viruses can retard break repairs, whatever the causes. The results imply proactive treatment and prevention of herpes viral infections may benefit BRCA mutation carriers.

scholarly journals In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur near Herpes Tumor Virus Sequences

2021 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Viral Infections ◽  
Sequence Data ◽  
Fragile Sites ◽  
Breast Cancers ◽  
Chromosome 4 ◽  
Brca1 And Brca2 ◽  
Independent Evidence ◽  
Chromosome Breaks

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosomes may not be restored correctly, allowing breaks to persist or rearrange chromosomes. These abnormalities are potentially catastrophic events that can originate from viral infections. I used bioinformatic analyses of publicly available breast cancer patient data to show that the distribution of chromosome breaks in hereditary breast cancers differs markedly from sporadic breast cancers. Then I tested hereditary breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had decisive matches to Epstein-Barr virus (EBV / HHV4) tumor variants HKHD40 and HKNPC60. Many breakpoints were near EBV genome anchor sites, human EBV tumor-like sequences, EBV-associated epigenetic marks, and some fragile sites. On chromosomes 2 and 12, sequences near EBV genome anchor sites accounted for 90% and 88% of breakpoints (p&lt;0.0001), respectively. On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences in 19 hereditary breast cancers. In contrast, 19 sporadic breast cancers only had 12 interchromosomal breakpoint regions on chromosome 4 near EBV-like sequences. On various other chromosomes, five EBV genome anchor sites were near hereditary breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Independent evidence further implicating EBV in hereditary breast cancer breakpoints is that 25 breast cancer break positions are within 1.25% of breakpoints in model EBV cancers. In addition to BRCA1 or BRCA2 mutations, all the hereditary breast cancers had mutated genes essential for immune responses. This compromise facilitates reactivation of herpes viruses which produce nucleases capable of breaking chromosomes. EBV also causes other deleterious effects: anchored EBV episomes can interfere with normal replication and obstruct DNA break repairs; even very early infection causes massive transcription changes. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

scholarly journals Update on chemoprevention in BRCA1 and BRCA2 mutation carriers

2005 ◽  
Vol 8 (9) ◽  
Author(s):  
M. Stumacher ◽  
S. M. Domchek
Keyword(s):  
Breast Cancer ◽  
Prophylactic Mastectomy ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Prophylactic Oophorectomy ◽  
Estrogen Exposure ◽  
Mutation Carriers ◽  
Increased Risk

Chemoprevention with tamoxifen and oophorectomy are thought to be effective in decreasing the incidence of breast cancer in women at increased risk for the disease. There is mounting data supporting the idea that hormonal interventions that reduce estrogen exposure to breast epithelium, such as prophylactic oophorectomy and tamoxifen, are effective in breast cancer prevention in both BRCA1 and BRCA2 mutations carriers. Several recent studies directly address the protective effect of tamoxifen and oophorectomy in BRCA mutation carriers and suggest that these endocrine manipulations decrease the risk of primary and secondary breast cancers. Ongoing studies aim to better define the effect of tamoxifen in these very high-risk women and determining whether factors, such as earlier age of use or prior prophylactic oophorectomy, impact tamoxifen's effect. Based on existing data, we recommend that women with deleterious mutations in BRCA1 or BRCA2 be informed of the beneficial effect of oophorectomy on breast cancer risk and that women who choose breast cancer screening instead of prophylactic mastectomy be offered tamoxifen as a prevention option.

scholarly journals Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience

2011 ◽  
Vol 29 (28) ◽  
pp. 3739-3746 ◽  
Author(s):  
Banu Arun ◽  
Soley Bayraktar ◽  
Diane D. Liu ◽  
Angelica M. Gutierrez Barrera ◽  
Deann Atchley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Pathologic Complete Response ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Neoadjuvant Systemic Therapy ◽  
Brca1 Carriers ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations ◽  
Brca1 Status

Purpose To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations. Patients and Methods A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival. Results Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not. Conclusion BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.

Breast cancer detection among Irish BRCA1 and BRCA2 mutation carriers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12038-e12038 ◽  
Author(s):  
Elaine Walsh ◽  
Michael P. Farrell ◽  
Fergal Gallagher ◽  
Roisin Clarke ◽  
Carmel Nolan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Interval Cancer ◽  
Breast Cancers ◽  
Interval Cancers ◽  
Brca1 And Brca2 ◽  
Clinical Breast Exam ◽  
Mutation Carriers ◽  
Clinical Breast

e12038 Background: High-risk breast cancer screening for BRCA1/2 mutations carriers with clinical breast exam, mammography and MRI have sensitivities approaching 100%. Even with intensive screening BRCA mutation carriers can present with self-detected interval cancers. We investigate screening practices and presentation among a cohort of Irish BRCA1/2 mutation carriers. Methods: Females with breast cancer belonging to kindreds now known to harbour BRCA1/2 mutations were retrospectively identified. Records were reviewed for BRCA mutation, demographics, breast cancer diagnosis, stage, histology and screening. We assessed screening modalities and whether breast cancers were diagnosed at screening or as interval cancers. Results: 53 cases of breast cancer were diagnosed from 1968-2010 among 53 Irish hereditary breast ovarian cancer kindreds. BRCA mutation status was unknown at time of diagnosis but subsequently confirmed. Detection method was identified in 50% of patients: 84% by clinical breast exam (CBE), 4% mammography, 4% MRI and 8% by a combination of CBE and mammography. Fifteen women (28%) developed second breast cancer; 9(60%) were undergoing screening, 2 were not and 27% were unknown. 22% were detected by CBE alone; 34% mammography; 22% a combination of mammography and CBE and 22% by MRI. In 41%, histology changed between first and second diagnosis. Two women developed a third breast cancer. In one, her second was an interval cancer despite being in a screening programme. Her third was radiologically detected. Conclusions: In this cohort of Irish BRCA1/2 mutation carriers almost 25% of second breast cancers were not detected by screening. 4% of cases were phenocopies and in 41% histology changed between first and second diagnosis. [Table: see text]

Breast cancer detection among Irish BRCA1 and BRCA2 mutation carriers.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 59-59
Author(s):  
Elaine Walsh ◽  
Michael P. Farrell ◽  
Fergal Gallagher ◽  
Roisin Clarke ◽  
Carmel Nolan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Interval Cancer ◽  
Breast Cancers ◽  
Interval Cancers ◽  
Brca1 And Brca2 ◽  
Clinical Breast Exam ◽  
Mutation Carriers ◽  
Clinical Breast

59 Background: High-risk breast cancer screening for BRCA1/2 mutations carriers with clinical breast exam, mammography and MRI have sensitivities approaching 100%. Even with intensive screening BRCA mutation carriers can present with self-detected interval cancers. We investigate screening practices and presentation among a cohort of Irish BRCA1/2 mutation carriers. Methods: Females with breast cancer belonging to kindreds now known to harbour BRCA1/2 mutations were retrospectively identified. Records were reviewed for BRCA mutation, demographics, breast cancer diagnosis, stage, histology and screening. We assessed screening modalities and whether breast cancers were diagnosed at screening or as interval cancers. Results: 53 cases of breast cancer were diagnosed from 1968-2010 among 53 Irish hereditary breast ovarian cancer kindreds. BRCA mutation status was unknown at time of diagnosis but subsequently confirmed. Detection method was identified in 50% of patients: 84% by clinical breast exam (CBE), 4% mammography, 4% MRI and 8% by a combination of CBE and mammography. Fifteen women (28%) developed second breast cancer; 9(60%) were undergoing screening, 2 were not and 27% were unknown. 22% were detected by CBE alone; 34% mammography; 22% a combination of mammography and CBE and 22% by MRI. In 41%, histology changed between first and second diagnosis. Two women developed a third breast cancer. In one, her second was an interval cancer despite being in a screening programme. Her third was radiologically detected. Conclusions: In this cohort of Irish BRCA1/2 mutation carriers almost 25% of second breast cancers were not detected by screening. 4% of cases were phenocopies and in 41% histology changed between first and second diagnosis. [Table: see text]

scholarly journals Chromosome breaks in breast cancers occur near herpes tumor virus sequences

2021 ◽  
Author(s):  
Bernard A Friedenson
Keyword(s):  
Breast Cancer ◽  
Binding Sites ◽  
Breast Cancers ◽  
Entire Genome ◽  
Barr Virus ◽  
Chromosome Breaks ◽  
Tumor Virus ◽  
Myc Gene ◽  
Epstein Barr ◽  
Bridge Models

This work finds viral DNA associates with most chromosome breaks in breast cancer and provides a mechanism for why this is so. Nearly 2000 breast cancers were compared to known Epstein Barr virus (EBV) variant cancers using publicly available data. Breast cancer breakpoints on all chromosomes cluster around the same positions as in nasopharyngeal cancers (NPCs), cancers 100 per cent associated with EBV variants. Breakpoints also gather at the same differentially methylated regions. Breast cancer further has an EBV methylation signature shared with other cancers that inactivates complement. Another known EBV cancer (Burkitt lymphoma) has distinctive MYC gene breakpoints surrounded by EBV like DNA. EBV like DNA consistently surrounds breast cancer breakpoints, which are often near known EBV binding sites. EBV explains why a break in a chromosome does not simply reconnect in breakage fusion bridge models, but instead destabilizes the entire genome. This work does not prove EBV variants cause breast cancer, but establishes links to high risk chromosome breaks and other changes.

scholarly journals Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer

2018 ◽  
pp. JGO.18.00066 ◽  
Author(s):  
Omalkhair Abulkhair ◽  
Mohammed Al Balwi ◽  
Ola Makram ◽  
Lamia Alsubaie ◽  
Medhat Faris ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Novel Mutation ◽  
Brca Mutation ◽  
Brca1 Gene ◽  
Brca1 And Brca2 ◽  
Brca1 Mutations ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations ◽  
Saudi Patients

Purpose Over the past three decades, the incidence rate of breast cancer (BC) among Arab women has continually increased. However, data on the prevalence of BRCA1/2 mutations are scarce. Although the population in Saudi Arabia is at large homogeneous and consanguinity is common, especially in the central, eastern, and southern regions of the country, the prevalence of BRCA1 and BRCA2 mutations and the characteristics of BC are not well studied in the country. Methods This prospective observational study intended to determine the prevalence of BRCA1 and BRCA2 mutations and sought to examine the clinicopathologic features of BC associated with these mutations. Results Of 310 patients, 270 (87%) had no mutation. BRCA mutations were identified in 40 patients; BRCA1 mutations were found in 11% of patients, and BRCA2 mutations were found in 2% of patients. Variants of unknown significance were found in 15% of patients (45 patients). Triple-negative BC (TNBC) accounted for 86% of all patients with BC and mutations. The following three recurrent deleterious founder BRCA1 mutations were observed: c.4136_4137delCT was observed in five unrelated patients, c.5530delC was observed in three unrelated patients, and c.4524G>A mutations were observed in five unrelated patients. One novel mutation was identified in the BRCA1 gene (c.5512 dup [p.Glu1838Glyfs*42]). Conclusion Among high-risk Saudi patients with BC, BRCA1 mutations are prevalent (11%). TNBC is the most common BC subtype. Furthermore, age alone does not have a significant association with mutation, but a combination of risk factors such as age, familial history, and TNBC has a significant association with BRCA mutation.

Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22065-e22065 ◽  
Author(s):  
R. Wesolowski ◽  
A. G. Shealy ◽  
J. Tao ◽  
H. C. Moore
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Brca Mutation ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Mutation Status ◽  
Hormone Receptor Positive ◽  
History Of

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.

Experience with nipple-sparing mastectomy after prior whole-breast radiation.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 173-173
Author(s):  
Aimee Marlena Mackey ◽  
Bret Taback ◽  
Preya Ananthakrishnan ◽  
Sheldon M. Feldman
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Breast Cancers ◽  
Ipsilateral Breast ◽  
Immediate Reconstruction ◽  
Areola Complex ◽  
Nipple Sparing Mastectomy ◽  
Nipple Sparing ◽  
Good Cosmesis

173 Background: Nipple-sparing mastectomy (NSM) is being performed more frequently for risk reduction and breast cancer treatment. Prior whole breast irradiation (WBI) has been considered a contraindication to NSM. This study reviews our NSM experience following prior WBI. Methods: We reviewed our prospective mastectomy database from April 2007 to April 2012 for patients undergoing NSM. Ten patients out of a total 169 NSM were identified that underwent NSM following prior WBI. Data collected included incision type, follow-up, complications, cosmesis, and recurrence. Results: Of the ten NSM patients who received prior WBI, 6 had recurrent ipsilateral breast cancer at the lumpectomy site, 3 developed contralateral breast cancers and opted for bilateral NSM, and 1 patient opted for bilateral NSM after finding a BRCA mutation following BCT. Mean patient age was 53. Two patients had comorbities: 1 hyperlipidemia and 1 former smoker. Three of 10 (30%) developed complications, with 2 partial necrosis of nipple-areola complex (NAC) and 1 complete loss of the NAC (Table). No patient required return to the operating room (local resection in the office was performed for the complete NAC loss) and all patients had good final cosmesis. All patients underwent immediate reconstruction: 5 tissue expanders (TE), 2 DIEP and 3 TRAM flaps. Mean follow up is 23 months with no local recurrences to date. Conclusions: This study demonstrates that NSM with immediate reconstruction can be performed in selected patients with prior WBI with an acceptable rate of nipple preservation and good cosmesis. NAC preservation is the ultimate goal in patients undergoing NSM. Current studies are ongoing to identify risk factors that may be associated with nipple necrosis. [Table: see text]

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