Inherited Cancer Susceptibility:

DNA Repair Genes

Dr. Tariq S. H. Al Jabry
Department of Genetics
College of Medicine and Health Sciences (COMHS)

tariqaljabry@squ.edu.om
 Cancer in Families
• All individuals are at risk of some type of cancer at some point in
their life.

• Some genetic disorders may increase the risk to certain cancers.

• Hereditary cancer syndromes represent 5-10 % of all cancers (Nagy

et al, 2004).

• They usually occur due to mutations in a single gene (i.e. Mendelian

pattern of inheritance).
Cancer in Families

Nussbaum et al, 2016

Inherited Cancer Susceptibility

Fostira et al, 2007

 Hereditary Breast and Ovarian Cancer
• BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2)
mutations

• Tumour suppressor genes

• Autosomal dominant disease

• Age of onset: Adulthood

Nussbaum et al, 2016

 Hereditary Breast and Ovarian Cancer:
Disease Aetiology and Prevalence
• Mutations in major cancer predisposing genes in general (including BRCA1 and
BRCA2) account for 3-10% of all breast cancer cases.

• Although BRCA mutations account for a small fraction of breast cancer cases overall,
they do account for approximately 70-80% of familial breast cancer cases.

• In families with a history of breast and ovarian cancer: ~2/3 carry a BRCA1 mutation.

• In families with a history of male and female breast cancer: ~2/3 of families carry a
BRCA2 mutation.

• In the Arab region >1/5 (20%) of hereditary breast cancer and/or ovarian cancer
patients are likely to have BRCA mutations (Abdulrashid et al, 2019).
 Hereditary Breast and Ovarian Cancer:
BRCA mutational profile
• Truncation variants are marked
in black (nonsense and
frameshift).

• Missense and synonymous

variants are marked in green.

• In-frame deletion variants are

marked in brown.

Concolino et al, 2019

 Hereditary Breast and Ovarian Cancer:
Pathogenesis

• BRCA1 and BRCA2 code for ubiquitously expressed nuclear

proteins that maintain genomic integrity by regulating DNA repair.

• Mutations that lead to a loss of BRCA1 or BRCA2 function permits

the accumulation of other mutations in the genome.

• The accumulation of mutations are directly responsible for neoplasia.

 DNA repair: Double Strand Breaks
• DNA double-strand break (DSB) repairs are
carried out by two mechanisms that differ in their
fidelity: non-homologous end joining (NHEJ)
and homologous recombination (HR).

• NHEJ, activated during G1 phase, does not rely

on a template strand for repairs, and is therefore
error-prone.

• HR, activated during S-G2 phase, enables the

accurate repair of DSB by using the intact sister
chromatid as a template for repair.

Dos Santos et al, 2020

 DNA repair: Double Strand Breaks

• In M phase, both HR and NHEJ repair are

reduced.

• Single-strand annealing (SSA), a DNA damage

repair mechanism that uses homologous repeats
to bridge DSB ends, is used to repair DSBs.

• SSA results in deletions and rearrangements

between repeats resulting in large-scale
chromosomal rearrangements

• HR is therefore the most accurate DSB repair

mechanism that maintains sequence integrity

Dos Santos et al, 2020

 Homologous Recombination Repair
• The MRN complex (MRE11-RAD50-NBS1) detects
DSBs and recruits Ataxia Telangiectasia Mutated
(ATM) kinase

• Inactive ATM dimers then dissociate into active

monomers through autophosphorylation

• Active ATM phosphorylates and activates

downstream DNA repair pathway proteins including
BRCA1.

• The phosphorylation of BRCA1 by ATM induces

its recruitment to DSBs and its interaction with
other DNA repair proteins.

• BRCA1 and 2 are key components of the HR

pathway that cooperate with other proteins to fix
DSBs.
Dos Santos et al, 2020
 Homologous Recombination Repair

• Active ATM monomers phosphorylate H2AX histones in

regions of DSBs and create a platform to recruit
BRCA1.

• BRCA1 facilitates a shift NHEJ to HR.

• The CtBP-Interacting Protein (CtIP), in conjunction

with the MRN complex, catalyses 5′-3′ resection at
DSBs to generate single-stranded DNA (ssDNA).

• The resulting ssDNA is then covered by Replication

Protein A (RPA) to protect the single strand.

• Further resection is completed by EXOnuclease 1

(EXO1) and DNA2 nuclease/helicase in cooperation
with BLoom syndroMe preotein (BLM) helicase.

Wu et al, 2020
 Homologous Recombination Repair
• Partner And Localiser of Bcl 2 (PALB2) is
phosphorylated by ATR and Chk1 kinase, which
accelerates its recruitment to sites of damage where it
recruits BRCA2.

• PALB2 and BRCA2 further promote RPA removal and

RAD51 loading.

• The resulting RAD51-ssDNA filament invades the intact

sister chromatid and extends the strand with the help of
DNA polymerase δ/η/κ.

• DNA polymerases δ (delta), η (eta), and κ (kappa) then

contribute to the synthesis of the new strands

• Finally the ligation of the double strands is carried out by

DNA ligase I.

Wu et al, 2020
 Hereditary Breast and Ovarian Cancer:
Phenotype and Natural History

• BRCA mutations are autosomal dominant

• The overall penetrance of breast cancer and ovarian cancer in female

carriers of BRCA1 germline mutations is estimated to be ~50-80%

• For BRCA2 mutations the penetrance is 40% for breast cancer and
10% for ovarian cancer.
 Phenotype and Natural History
• In addition to an increased risk of ovarian and female breast cancer,
individuals with BRCA germline mutations are also susceptible to
other cancers.

• BRCA1 mutations convey an increased risk to prostate cancer,

melanoma, and possibly colon cancer.

• Germline mutations in BRCA2 increase the risk of prostate,

pancreatic, bile duct, gallbladder, melanoma, and male breast
cancer.
 Hereditary Breast and Ovarian Cancer:
Management and Inheritance Risk
Management:
• Women with a germline BRCA mutations include frequent breast and ovarian examinations as
well as imaging studies.

• Management of at-risk males includes frequent prostate and breast examinations and
laboratory tests for evidence of prostate cancer.

• Other than surveillance, prophylaxis is also an option, where bilateral mastectomies and
salpingo-oophorectomies may reduce the risk of breast and ovarian cancer respectively by more
than 90%.

Inheritance Risk:
• The offspring of a parent who carries a BRCA mutation has a 50% risk of inheriting that mutation.
 Genetic testing
• The identification of a genetic predisposition in a family is of utmost
importance for the clinical management of the disease.

• Individuals with a hereditary predisposition require genetic testing

and counselling.

• Affected individuals may then be offered intensive monitoring and

therapy.
Questions?