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

Mapping Intimacies ◽

10.20944/preprints202107.0430.v1 ◽

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<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.

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

10.20944/preprints202105.0490.v1 ◽

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.

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

10.1101/2021.04.19.440499 ◽

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.

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Gene Mutations in Hereditary Breast Cancer- A Review

European Journal of Medical and Health Sciences ◽

10.24018/ejmed.2020.2.3.286 ◽

2020 ◽

Vol 2 (3) ◽

Author(s):

Pathima Fairoosa ◽

Chamindri Witharana

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Cancer Susceptibility ◽

Gene Mutations ◽

Tumour Suppressor Genes ◽

Breast Cancers ◽

Germline Gene ◽

Brca1 And Brca2 ◽

Repair Gene ◽

Cancer Susceptibility Genes

The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

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Genotype/Phenotype Correlations in Patients with Hereditary Breast Cancer

Breast Care ◽

10.1159/000380900 ◽

2015 ◽

Vol 10 (1) ◽

pp. 22-26 ◽

Cited By ~ 6

Author(s):

Maike Wittersheim ◽

Reinhard Büttner ◽

Birgid Markiefka

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Hereditary Breast Cancer ◽

Sporadic Breast Cancer ◽

Germline Mutations ◽

Breast Cancers ◽

High Susceptibility ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Distinct Morphology

Of all breast cancer cases, 5-10% can be attributed to germline mutations, and the high-susceptibility genes BRCA1 and BRCA2 account for about 25-28% of these cases. For the remainder, several genes of moderate and low penetrance have been discovered. Histopathologic characteristics have been studied in small cohorts, but for most of the known non-BRCA1/2-associated hereditary breast cancers, the histologic and immunohistochemical phenotypes are not yet identified. Particularly BRCA1 tumors are associated with a distinct morphology and immunohistochemical characteristics that differ from sporadic breast cancer of age-matched controls. The recognition of features characteristic of these mutations can be helpful to identify patients likely to carry a germline mutation and to assess which gene should be screened for first, in families with a high occurrence of breast and ovarian cancer.

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