BIOLOGY

PROJECT
STUDYING BRCA GENE
MUTATION
AND RISKS OF VARIOUS
CANCERS ASSOCIATED
BY: DEVASHISH
SHARMA

KENDRIYA VIDYALAYA RWF

YELAHANKA NEW TOWN
BANGLAORE-560064

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 KENDRIYA VIDYALAYA
W

YELAHANKA NEW TOWN

BANGALORE-560064

CENTRAL BOARD OF SECONDARY

EXAMINATIONS –DELHI

TOPIC:

STUDYING BRCA GENE MUTATION

AND RISKS OF VARIOUS CANCERS
ASSOCIATED
Name: DEVASHISH SHARMA

Class: XII A

Roll No:

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 DEPARTMENT OF
BIOLOGY
KENDRIYA VIDYALAYA RWF YELAHANKA
BANGALORE -560064

CERTIFICATE
This is to certify that DEVASHISH SHARMA of class XII
has successfully completed the investigatory project on the
topic “STUDYING BRCA GENE MUTATION AND RISKS
OF VARIOUS CANCERS ASSOCIATED” under the
guidance of Dr(Mrs) P Subbalakshmi PGT(Biology)
during the academic session 2019-20 towards the partial
fulfilment of the Biology Practical Examination conducted
by CBSE .

Internal Examiner External Examiner

Signature of Principal

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 ACKNOWLEDGEMENT

I would like to express my special thanks to my teacher

Dr(Mrs) P Subbalakshmi PGT(Biology) who gave me an
opportunity to do this wonderful project on the topic
“STUDYING BRCA GENE MUTATION AND RISKS
OF VARIOUS CANCERS ASSOCIATED”.This helped me
in doing a lot of research on the topic by interacting with
friends, scholars etc. I also express my sincere gratitude to
my Principal Dr(Mrs). Pushpa Rani Yadav. I further
acknowledge my heartfelt thanks to my parents, scholars,
and friends, who helped me a lot in finalizing this project
within the limited time frame.

DEVASHISH SHARMA
XII A
KV RWF

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CONTENTS

1.What are BRCA1 and BRCA2?

2.Cancers linked to harmful variants in
BRCA1 & BRCA2
3.Inherited mutations across specific
population groups
4.BRCA1 & BRCA2 Genetic tests
5.Supressing the effects of gene mutation

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WHAT ARE BRCA1 AND
BRCA2:

-BRCA1 (BReast CAncer gene 1) &

BRCA2 (BReast CAncer gene 2)
are genes that produce proteins that
help repair damaged DNA. Everyone
has two copies of each of these genes—
one copy inherited from each
parent. BRCA1 and BRCA2 are
sometimes called tumor suppressor
genes because when they have certain
changes, called harmful (or pathogenic)
variants (or mutations), cancer can
develop.

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-BRCA1- and BRCA2-associated
hereditary breast and ovarian cancer is
inherited in an autosomal
dominant manner. The vast majority of
individuals with
a BRCA1 or BRCA2 pathogenic
variant have inherited it from a parent.

-People who inherit harmful variants in

one of these genes have increased risks
of several cancers—most notably breast
and ovarian cancer, but also several
additional types of cancer. People who
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have inherited a harmful variant
in BRCA1 and BRCA2 also tend to
develop cancer at younger ages than
people who do not have such a variant.

-A harmful variant
in BRCA1 or BRCA2 can be inherited
from either parent. Each child of a
parent who carries any mutation in one
of these genes has a 50% chance (or 1
in 2 chance) of inheriting the mutation.
Inherited mutations—also
called germline mutations or variants—
are present from birth in all cells in the
body.  

-Even if someone has inherited a

harmful variant
in BRCA1 or BRCA2 from one parent,
they would have inherited a normal
copy of that gene from the other parent
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(that’s because in most cases, embryos
with a harmful variant from each parent
cannot develop). But the normal copy
can be lost or change in some cells in
the body during that person’s lifetime.
Such a change is called a somatic
alteration. Cells that don’t have any
functioning BRCA1 or BRCA2 proteins
can grow out of control and become
cancer.

CANCERS LINKED TO
HARMFUL VARIANTS OF
BRCA1 & BRCA2:
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-A woman’s lifetime risk of
developing breast and/or ovarian
cancer is markedly increased if she
inherits a
harmful variant in BRCA1 or BRCA2,
but the degree of increase varies
depending on the mutation.

Breast cancer: About 13% of women

in the general population will develop
breast cancer sometime during their
lives. By contrast, 55%–72% of
women who inherit a
harmful BRCA1 variant and 45%–69%
of women who inherit a
harmful BRCA2 variant will develop
breast cancer by 70–80 years of age.
The risk for any one woman depends
on a number of factors, some of which
have not been fully characterized. 

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-Like women with breast cancer in
general, those with
harmful BRCA1 or BRCA2 variants
also have an increased risk of
developing cancer in the opposite
(contralateral) breast in the years
following a breast
cancer diagnosis . The risk of
contralateral breast cancer increases
with the time since a first breast
cancer, reaching 20%–30% at 10 years
of follow-up and 40%–50% at 20
years, depending on the gene
involved.

-Ovarian cancer: About 1.2% of

women in the general population will
develop ovarian cancer sometime
during their lives . By contrast, 39%–
44% of women who inherit a
harmful BRCA1 variant and 11%–17%
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 of women who inherit a
harmful BRCA2 variant will develop
ovarian cancer by 70–80 years of age .

-Harmful variants
in BRCA1 and BRCA2  increase the
risk of several additional cancers. In
women, these include fallopian tube
cancer and primary peritoneal
cancer both of which start in the same
cells as the most common type of
ovarian cancer. Men
with BRCA2 variants, and to a lesser
extent BRCA1 variants, are also at
increased risk of breast cancer
and prostate cancer .Both men and
women with
harmful BRCA1 or BRCA2 variants are
at increased risk of pancreatic cancer,
although the risk increase is low.

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-In addition, certain variants in BRCA1 
and BRCA2 can cause subtypes
of Fanconi anemia, a rare syndrome
that is associated with childhood solid
tumors and development of acute
myeloid leukemia . The mutations that
cause these Fanconi anemia subtypes
have a milder effect on protein function
than the mutations that cause breast and
ovarian cancer. Children who inherit
one of these variants from each parent
will develop Fanconi anemia.  

INHERITED MUTATIONS
ACROSS SPECIFIC
POPULATIONS:
-The likelihood of carrying
an inherited mutation
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in BRCA1 or BRCA2 (the prevalence)
varies across specific population
groups. While the prevalence in the
general population is about 0.2%–0.3%
(or about 1 in 400), about 2.0% of
people of Ashkenazi Jewish descent
carry a harmful variant in one of these
two genes and the variants are usually
one of three specific variants, called
founder mutations. Other populations,
such as Norwegian, Dutch, and
Icelandic peoples, also have founder
mutations .

-Different racial/ethnic and

geographic populations also tend to
carry different variants in these genes.
For instance, African Americans
have BRCA1 variants that are not seen
in other racial/ethnic groups in the
United States. Most people of
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Ashkenazi Jewish descent in the United
States who carry a BRCA variant have
one of three specific variants (two
in BRCA1 and one in BRCA2). In the
Icelandic population, a different variant
in BRCA1 is common among those who
inherit a mutation in BRCA1. 

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BRCA-1 & BRCA-2
GENETIC TESTS:
-BRCA1 and BRCA2 mutation testing
can give several possible results: a
positive result, a negative result, or
a variant of uncertain
significance (VUS) result.

-Positive result. A positive test

result indicates that a person has
inherited a known harmful variant
in BRCA1 or BRCA2 (these are
typically called “pathogenic” or “likely
pathogenic” variants on laboratory test
reports) and has an increased risk of
developing certain cancers. However, a
positive test result cannot tell whether
or when the tested individual will
develop cancer. Some people who
inherit a
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harmful BRCA1 or BRCA2 variant
never develop cancer.
A positive test result may also have
important implications for family
members, including future
generations.
 Both men and women who inherit a
harmful BRCA1 or BRCA2 variant,
whether or not they develop cancer
themselves, may pass the variant to
their children. Each child has a 50%
chance of inheriting a parent’s
variant.
 All blood relatives of a person who
has inherited a
harmful BRCA1 or BRCA2 variant are
at some increased risk of having the
variant themselves. For example, each
of that person’s full siblings has a

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 50% chance of having inherited the
variant as well.
 Very rarely, an individual may test
positive for a harmful variant not
inherited from either parent. This is
called a de novo (or “new”) variant.
Such a variant is one that arose in
a germ cell (sperm or egg) of one of
the parents and is present in all the
cells of the person who grew from
that cell. The children of someone
with a de novo variant (but not his or
her siblings) are at risk of inheriting
the variant.

-Negative result. A negative test

result can have several meanings,
depending on the personal and family
medical history of the person who is
tested and whether or not a harmful
mutation has already been identified in
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the family. If a close blood relative of
the tested person is known to carry a
harmful BRCA1 or BRCA2 variant, a
negative test result is clear: it means the
tested person did not inherit the harmful
variant that is present in the family and
cannot pass it to their children. A
person with such a test result, called a
true negative, has a risk of cancer that
is similar to that of someone in the
general population. However, there are
other factors besides genetic factors that
may increase the risk of cancer, such
as radiation exposures at an early age,
and those factors should be considered
in assessing their risk of cancer. 
If the tested person has no personal
history of cancer and their family isn’t
known to carry a harmful variant, then
in this case, a negative test result is
considered to be “uninformative.”
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There are several possible reasons why
someone could have an uninformative
negative test result:
 Without testing family members who
have had cancer, it is uncertain
whether the negative test means that
the person did not inherit
a BRCA1 or BRCA2 mutation that is
present in the family or whether the
family history might be due to a
mutation in another gene that was not
tested or to other, nongenetic risk
factors.
 The individual may have a harmful
variant that is not detectable by
current testing technologies.
 Rarely, there could be an error in the
testing, either because inappropriate
tests were recommended or ordered,
genetic variants were interpreted

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 incorrectly, or the wrong results were
relayed to patients .

-Variant of Uncertain Significance

(VUS) result. Sometimes, a genetic test
finds a change
in BRCA1 or BRCA2 that has not been
previously associated with cancer and is
uncommon in the general population.
This type of test result is called “a
variant of uncertain significance,” or
VUS, because it isn’t known whether
this specific genetic change is harmful.
As more research is conducted and
more people are tested
for BRCA1 and BRCA2 variants,
scientists will learn more about
uncertain changes and cancer risk.
Clinicians and scientists are actively
working to share information on these
mutations so that they can be
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reclassified as either clearly harmful or
clearly not harmful.

SUPPRESSING THE
EFFECTS OF GENE
MUTATION:
-Several options are available for
reducing cancer risk in individuals who
have inherited a harmful BRCA1 or
BRCA2 variant. These include
enhanced screening, risk-reducing
surgery (sometimes referred to as
prophylactic surgery), and
chemoprevention.
-Enhanced screening: Some women
who test positive for harmful BRCA1
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and BRCA2 variants may choose to
start breast cancer screening at younger
ages, have more frequent screening than
is recommended for women with an
average risk of breast cancer, or have
screening with magnetic resonance
imaging (MRI) in addition to
mammography.
-No effective ovarian cancer screening
methods are known. Some groups
recommend transvaginal ultrasound,
blood tests for the CA-125 antigen
(which can be present at higher-than-
normal levels in women with ovarian
cancer), and clinical examinations for
ovarian cancer screening in women
with harmful BRCA1 or BRCA2
variants. However, none of these
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methods appear to detect ovarian
tumors at an early enough stage to
improve long-term survival (28).
The National Comprehensive Cancer
Network (NCCN) guidelines
recommend that men with harmful
germline variants in BRCA1 or BRCA2
consider having a discussion with their
doctor about prostate-specific antigen
(PSA) testing for prostate cancer
screening starting at age 40 .

Some experts recommend the use of

ultrasound or MRI/magnetic retrograde
cholangiopancreatography to screen for
pancreatic cancer in people who are
known to carry a harmful BRCA1 or
BRCA2 variant and who have a close
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blood relative with pancreatic cancer .
However, it is not yet clear whether
pancreatic cancer screening and early
pancreatic cancer detection reduces the
overall risk of dying from a pancreatic
cancer.
All of these screening approaches have
potential harms as well as possible
benefits. For example, MRI is more
likely than mammography to result in
false-positive findings. And there is
some concern that women who have a
harmful BRCA variant might be
particularly sensitive to the DNA-
damaging effects of tests that involve
radiation (such as mammography)
because they already have a defect in
DNA repair .
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Risk-reducing surgery. Risk-reducing,
or prophylactic, surgery involves
removing as much of the "at-risk" tissue
as possible. Women may choose to
have both breasts removed (bilateral
risk-reducing mastectomy) to reduce
their risk of breast cancer. Surgery to
remove a woman's ovaries and fallopian
tubes (bilateral risk-reducing salpingo-
oophorectomy) can help reduce her risk
of ovarian cancer. (Ovarian cancers
often originate in the fallopian tubes, so
it is essential that they be removed
along with the ovaries.) Removing the
ovaries may also reduce the risk of
breast cancer in premenopausal women
by eliminating a source of hormones

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that can fuel the growth of some types
of breast cancer.
-These surgeries are irreversible, and
each has potential complications or
harms. These include bleeding or
infection, anxiety and concerns about
body image (bilateral risk-reducing
mastectomy), and early menopause in
premenopausal women (bilateral risk-
reducing salpingo-oophorectomy).
-Risk-reducing surgery does not
guarantee that cancer will not develop
because not all at-risk tissue can be
removed by these procedures. That is
why these surgical procedures are
described as “risk-reducing” rather than
“preventive.” Some women have
developed breast cancer, ovarian
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cancer, or primary peritoneal
carcinomatosis (a type of cancer similar
to ovarian cancer) even after risk-
reducing surgery. Nevertheless, these
surgical procedures greatly reduce risk.
For example, in several studies women
who underwent bilateral salpingo-
oophorectomy had a nearly 80%
reduction in risk of dying from ovarian
cancer, a 56% reduction in risk of dying
from breast cancer (32), and a 77%
reduction in risk of dying from any
cause during the studies’ follow-up
periods .
The reduction in breast and ovarian
cancer risk from removal of the ovaries
and fallopian tubes appears to be

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similar for carriers of BRCA1 and
BRCA2 variants .
Chemoprevention. Chemoprevention
is the use of medicines to reduce the
risk of cancer. Two chemopreventive
drugs (tamoxifen [Nolvadex] and
raloxifene [Evista]) have been approved
by the Food and Drug Administration
(FDA) to reduce the risk of breast
cancer in women at increased risk, but
the role of these drugs in women with
harmful BRCA1 or BRCA2 variants is
not yet clear. Data from three studies
suggest that tamoxifen may be able to
help lower the risk of breast cancer in
women who carry harmful variants in
BRCA2 (34) and of cancer in the
opposite breast among BRCA1 and
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BRCA2 variant carriers previously
diagnosed with breast cancer. Studies
have not examined the effectiveness of
raloxifene in BRCA1 and BRCA2
variant carriers specifically.
However, these medications may be an
option for women who choose not to, or
who cannot, undergo surgery. The
potential harms of these drugs include
menopausal symptoms, blood clots,
stroke, increased risk of endometrial
cancer (tamoxifen), and allergic
reactions (raloxifene).
Both women in the general population,
as well as those with harmful BRCA1
or BRCA2 variants, who have ever
used oral contraceptives (birth control
pills) have about a 50% lower risk of
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ovarian cancer than women who have
never used oral contraceptives .
Potential harms of oral
contraceptives include increased risk
of breast cancer, increased risk that a
human papillomavirus (HPV) infection
will become cervical cancer, and
possible cardiovascular effects among
older reproductive-age women.

FOR PEOPLE WHO HAVE

ALREADY DEVELOPED CANCER
DUE TO MUTATION IN GENE:
BRCA1 and BRCA2 genes are
involved in DNA repair, tumors with
alterations in either gene are
particularly sensitive to anticancer

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agents that act by damaging DNA, such
as cisplatin.

A class of drugs called PARP

inhibitors, which block the repair of
DNA damage, have been found to
arrest the growth of cancer cells that
have harmful BRCA1 or BRCA2
variants. Four PARP inhibitors—
olaparib [Lynparza], rucaparib
[Rubraca], niraparib [Zejula], and
talazoparib [Talzenna]—are approved
by the FDA to treat certain cancers
bearing harmful variants in BRCA1 or
BRCA2. (In some cases, these are used
whether or not a BRCA1 or BRCA2
mutation is present.)

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Breast cancers with harmful BRCA1
variants are more likely to be "triple-
negative cancers" (that is, the breast
cancer cells do not have estrogen
receptors, progesterone receptors, or
large amounts of HER2/neu protein)
than sporadic breast cancers or breast
cancers with harmful BRCA2 variants.
Triple-negative cancers are harder to
treat and have a poorer prognosis than
other types of breast cancers.
If someone has tumor genetic testing
that reveals the presence of a harmful
BRCA1 or BRCA2 variant in the
tumor, they should consider having a
germline genetic (blood) test to
determine if the variant was inherited.
Knowing if the variant was inherited is
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important for that individual to
understand their risks to potentially
develop other cancers in the future. It
can also determine if other family
members may be at risk of inheriting
the harmful variant.

BIBILOGRAPHY:
1. National Cancer Institute: BRCA Gene mutations:
Cancer Risk and Genetic testing.
2. Petrucelli N, Daly MB, Pal T. BRCA1- and
BRCA2-Associated Hereditary Breast and Ovarian
Cancer. 1998 Sep 4 [Updated 2022 May 26]. In:
Adam MP, Everman DB, Mirzaa GM, et al.,
editors. GeneReviews® [Internet]. Seattle (WA):
University of Washington, Seattle; 1993-2022.

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 Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1247/
3. JULIE, L. (2016). Methods to identify BRCA
testing in claims data. American Journal of
Obstetrics and Gynecology.
https://doi.org/10.1016/j.ajog.2016.03.049
4. HAGAN, M., MD, SMRZ, S. A., MD, & COHN, D.
E., MD,MBA (2020). Chemotherapy directly
followed by poly(ADP-ribose) polymerase
inhibition as an alternative to surgery in patients
with BRCA-mutated ovarian cancer: a potential
management strategy in the era of coronavirus
disease 2019. American Journal of Obstetrics and
Gynecology.
https://doi.org/10.1016/j.ajog.2020.05.037
5. Spannuth WA, Thaker PH, Sood AK. Concomitant
BRCA1 and BRCA2 gene mutations in an
Ashkenazi Jewish woman with primary breast and
ovarian cancer. Am J Obstet Gynecol. 2007
Apr;196(4):e6-9. doi: 10.1016/j.ajog.2007.01.026.
PMID: 17403394.
https://pubmed.ncbi.nlm.nih.gov/17403394/

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