Genetic testing and counseling can help determine cancer risk based on family history and genetic mutations. Most cancers are sporadic but 5-10% are hereditary due to inherited gene mutations. Genetic counselors use family histories and genetic tests to assess cancer risks, recommend screening, and provide counseling to relatives. While some cancers have clear high-risk genes, most have contributions from multiple common and rare variants, so interpretation requires expertise.

1. Cancer Genetics
SHOULD WE ALL GET OUR GENES PROFILED?
ASPEC / March 15, 2021 / Robert Miller MD

3. “the fault…is not in our stars but in ourselves”

4. To keep it simple
- Are the cancer genes inherited and run in families
(germ line and found in every cell in the body) or acquired during life
(somatic mutation, and only present in the malignant cells)?
- How can you tell them apart and which is more common?
- What is the role of a genetic counselor in making sense of a
worrisome family history and what tests would they recommend?

5. Francis Crick in
1958

6. Is Cancer a Genetic Disease?
Since the identification of Oncogenes that could turn normal cell into cancer
cells, it’s been assumed that finding and fixing the gene should solve this
problem…but
It’s more complicated
May be more than one gene associated with the cancer
May be that conventional genes (protein coding genes) are only part (a small
part) of the problem (epigenetics trumps genetics or microbiome genome)
May be that cancer is not a genetic problem but a metabolic problem

7. Complexity of Genetics
Human Genome Project has also led to a change in our understanding of human traits and how we teach
them - one example is eye color. For many years, students were taught that one dominant gene controlled
brown or blue eyes In fact, at least ten genes each of which comes in several "flavors," contribute to
eye color
Other traits are even more complicated; for example, around 80 percent of a person's height is controlled
by more than 700 genomic variants, each one having a very small influence.
www.genome.gov
The human genome contains approximately 3 billion of
these base pairs, which reside in the 23 pairs of
chromosomes within the nucleus of all our cells. Each
chromosome contains hundreds to thousands of genes,
which carry the instructions for making proteins. Each of
the estimated 30,000 genes in the human genome makes
an average of three proteins.

9. Protein coding genes make up only 1.5% of the genome

10. Humans may have far fewer genes than assumed - somewhere between 20,000 to
25,000.
That number sounds embarrassingly small considering that nematode worms have
about 20,000 too, grapes have about 30,000 and tomatoes have nearly 32,000.
Who has more
genes, us or a
tomato?

11. It’s not this simple!
Protein coding genes are a very small part of the picture
Tumor Evolution in the Transcriptome, Epigenome, and
Epitranscriptome

12. https://youtu.be/UQecetRMzWI

13. As cancer is evolving there are more changes going on in the epigenetic
modifications (methylation) than in the genes themselves
All cancers are epigenetically abnormal

15. Maybe cancer is
not genetic but
metabolic and
we should be
looking at the
mitochondria not
the nucleus.

16. Prof. Thomas Seyfried

17. Types of genes linked to cancer
Tumor suppressor genes. These are protective genes. Normally, they limit cell
growth by:
•Monitoring how quickly cells divide into new cells
•Repairing mismatched DNA
•Controlling when a cell dies
Examples of tumor suppressor genes include BRCA1, BRCA2, (inherited for breast cancer)
and p53 or TP53 (most commonly mutated gene in people with cancer and acquired)
Oncogenes. These turn a healthy cell into a cancerous cell. Mutations in these genes are not known to be
inherited.
Two common oncogenes are:
•HER2
•The RAS family of genes
DNA repair genes. These fix mistakes made when DNA is copied. Many of them function as tumor
suppressor genes. BRCA1, BRCA2, and p53 are all DNA repair genes and may be inherited or acquired

18. Two Questions about Genetics
and cancer
1. Did you inherit this (hereditary or germ line). From a
blood test or saliva. Tell you what other cancers to
expect and the need to have family testing.
2. Did the mutation occur after birth (acquired or somatic),
Find this from a genetic analysis of the cancer tissue
(biopsy or liquid biopsy) may predict how malignant and
what treatment drug options will be effective.

19. For prostate cancer it may be worth testing for inherited mutations (to help
predict the course of the disease and for family counseling) and cell molecular
genetics (to predict how malignant or aggressive the cancer is, does the
patient even need to be treated?)

21. For lung cancer it’s necessary to test for acquired mutations because it will
predict which drugs or immunotherapy approached may be useful.

23. Breast Cancer need both for familial or inherited testing (effects management as
well as family counseling) and somatic testing (impacts on specific treatment
decisions)

29. Paradox that triple
negative do better
with chemoRx if they
are BRCA + , also
BRCA do better with
PARP inhibitors and
the more mutations
the more likely to
respond to
immunotherapy

30. Which is more common, inherited
(hereditary) or acquired or somewhere
in between?
- Sporadic
- Familial Cancer
- Hereditary Cancer

31. Sporadic
Most cancers – 75% to 80% – are
sporadic. In sporadic cancer, the gene mutations
that cause the cancer are acquired (occur only in
the tumor cells, somatic) and are not inherited

32. Genetic analysis of
the cancer tissue to
find somatic or
acquired genetic
mutations.
EGFR mutation
found in lung
cancer will guided
the physician the
three drugs
currently approved
and effective for
cancers with this
type of mutation.

33. Familial Cancer
Certain common cancers, such as breast, prostate and
colon cancers, may occur in more than one member of the same
family, thought to be the result of multiple influences.
A combination of several genes and other factors, such as diet and
exercise, all contribute a small amount to an increased risk of
developing cancer. Such families may have a moderately increased
risk to develop cancer.

34. Hereditary Cancer Only 5% to 10% of all cancers are
hereditary and due to a gene mutation that is present from birth.
Usually, the mutation was passed from a mother or father to the
child. Because of this, there is usually a recognizable pattern of cancer on
one side of the family.
There are several clues which suggest that there is hereditary cancer in a family.
These can include:
- Age of diagnosis is usually younger than in sporadic forms of cancer (often
younger than age 50).
- Multiple family members have the same or related types of cancer.
- Cancer is more likely to develop in more than one site in the body.
- Rare cancers may occur, for example, male breast cancer.

35. February 4, 2021 N Engl J Med 2021; 384:440-451

36. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women
Breast Cancer Association Consortium
N Engl J Med 2021; 384:428-439
Among European women, approximately 6.8% of the patients and 2.0% of the controls had protein-truncating
variants in any of the 9 genes associated with breast cancer risk; in addition, 2.2% of the patients and 1.4% of
the controls had missense variants in CHEK2.
Estimated Absolute Risk of Breast Cancer
Associated with Protein-Truncating Variants in
8 Genes
We used a panel of 34
putative susceptibility
genes to perform
sequencing on samples
from 60,466 women with
breast cancer and
53,461 controls.

37. In the 90% of cancers that are sporadic it takes time to accumulate enough
mutations to get cancer

38. In the 10% of cancers that are hereditary every cell starts out with at least
one mutation so cancer is more likely and shows up more quickly

41. High-risk syndromic genes are
highlighted in green. The
moderate-penetrance genes
(highlighted in red) have an
approximate relative risk of 2.0.
The common, low-risk genes are
shown in orange.
Foulkes, N Engl J Med 2008;
359:2143-2153
Uncommon high risk mutations =
hereditary and more common
low risk gene mutations =
familial

42. A diagram showing the major cancer
genes for some cancers. The larger
the gene name, the more frequently
that gene is defective in that cancer
type.
Cancer Genes

43. •So far, 291 cancer genes have been
reported, more than 1% of all the
genes in the human genome.
•90% of cancer genes show somatic
mutations in cancer, 20% show
germline mutations and 10% show
both.
2004 Census of Known
Cancer Genes
Nat Rev Cancer. 2004 Mar; 4(3): 177–183.

44. http://atlasgeneticsoncology.org/Genes/Geneliste.html
Indexation date : Sun Feb 28 12:28:29 CET 2021

46. Cancer risk associated with
inherited BRCA1 mutations
Risks in women
•Breast cancer: The lifetime risk for a women with a BRCA1 mutation is about 65 percent compared to 12.5 percent for an
average risk woman.
•Ovarian cancer: The lifetime risk for a women with a BRCA1 mutation is about 40 percent compared with 1.3 percent for an
average risk woman.
•Second breast cancer in women who have already been diagnosed with breast cancer: The lifetime risk is about 40 percent.
•Uterine cancer: There is a slightly increased risk for a rare form of aggressive uterine cancer, the estimated risk to age 70 is less
than 5 percent
Risks in men
•Prostate cancer: The lifetime risk for a man with a BRCA1 mutation is about 16 percent compared to 12 percent for an average
risk man. Prostate cancers in men with inherited BRCA1 mutations may be more aggressive than in men without an inherited
mutation.
•Male breast cancer: The lifetime risk for a man with a BRCA1 mutation is about 2 percent.
Risks in both men and women
•Pancreatic cancer: The lifetime risk for a person with a BRCA1 mutation is about 5 percent compared to 1 percent for an average
risk person.
•Research on how mutations in the BRCA1 gene affect cancer risk is ongoing. Some research suggests that BRCA1 mutations
may increase risk for melanoma. However, because these studies are not conclusive, genetics experts often look at a person’s
family history of cancer to help people with BRCA1 mutations understand their risk for additional cancers.

47. In a moving New York Times op-ed,(March 24, 2015) Angelina Jolie Pitt revealed today that she had preventive
surgery last week to remove her ovaries and fallopian tubes. The news comes two years after she disclosed that
she had a preventive double mastectomy touching off a national conversation about women and cancer risk
Jolie Pitt carries a mutation in the BRCA1 gene that gives her an 87% chance of developing breast cancer and a
50% chance of developing ovarian cancer. She lost her mother, grandmother, and aunt to cancer.

49. Odds of having BRCA mutation
In the general population : (0.25%)
BRCA 1 ( 1 in 300) and BRCA 2 ( 1in 800)
Ashkenazi Jewish frequency of either is 1in 40 (2.5%)

50. Non-Ashkenazi Jewish ancestry
●Women with breast cancer (any age): 1 in 50 (2 percent)
●Women with breast cancer (younger than 40 years): <1 in 10 (<10 percent)
●Men with breast cancer (any age): 1 in 20 (5 percent)
●Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10 to 15 percent)
Ashkenazi Jewish ancestry
●Women with breast cancer (any age): 1 in 10 (10 percent)
●Women with breast cancer (younger than 40 years): approximately 1 in 3 (30 to 35
percent)
●Men with breast cancer (any age): 1 in 5 (19 percent)
●Women with ovarian cancer or primary peritoneal cancer (all ages): approximately 1 in 3
(36 to 41 percent)

51. Founder Population
Members of the Jewish community who trace their roots to Central or Eastern Europe are
known as Ashkenazi Jews.
Although today members of this community are found around the world, Ashkenazi Jews for
centuries were a geographically isolated population. The isolation experienced by this
population means its members can trace their ancestry back to a small number of members
known as “founders.”

52. The study in in the journal Nature Communications was funded by the National Institutes of Health and the National
Science Foundation, along with several private foundations.
Nat. Commun. 5:4835 doi: 10.1038/ncomms5835 (2014).

53. “Ashkenaz” in Hebrew refers to Germany, and Ashkenazi Jews are those who originated in Eastern Europe, no more than half
of their DNA comes from ancient Europeans. Those ancient people split off from the ancestors of today’s Middle Easterners
more than 20,000 years ago, with a founding group of about 3,500 to 3,900 people.
The rest of the Ashkenazi genome comes from the Middle East, this founding group “fused” with the European founding
group to create a population of 250 to 420 individuals. These people lived 25 to 32 generations ago, and their descendants
grew at a rate of 16% to 53% per generation, the researchers calculated.
Previous analyses of recent AJ history highlighted a narrow population bottleneck of only hundreds of individuals in late
medieval times, followed by rapid expansion.
Today there are more than 10 million Ashkenazi Jews around the world,
The AJ population is much larger and/or experienced a more severe bottleneck than other founder populations, such as
Amish, Hutterites or Icelanders, whose demographic histories facilitated a steady stream of
genetic discoveries.
Nat. Commun. 5:4835 doi: 10.1038/ncomms5835 (2014).

54. Final Recommendation Statement
BRCA-Related Cancer: Risk Assessment, Genetic
Counseling, and Genetic Testing
August 20, 2019
testing begin with a relative with known BRCA-related cancer or relative with the highest probability of mutation
should be tested. Because risk assessment is primarily based on family history, it is unclear how women with a
limited or unknown family history should be assessed
https://uspreventiveservicestaskforce.org/

55. What do you learn from seeing a genetic counselor?

56. Case study from Genetics Counselor at Mass
General
https://youtu.be/NRRws1OoT_g

57. Pedigree Chart to
map out the family
tree

67. Turns out she
has BRIP1
(ovarian
cancer gene)
and HOXB13
(prostate
cancer gene)

68. Then her uncle gets
tested and he has
both so he can
screen for prostate
cancer

69. Then her brother
gets tested and he
has prostate so he
can screen for
prostate cancer

70. Then her cousin
gets tested and he
is negative for both

73. I wouldn’t really recommend whole exome/genome sequencing for individuals with no medical indication to
do so. This does have to do with clinical utility and interpretation of data.
As for individuals who are adopted or would like more info about their health, I would recommend looking into
some proactive health panels. Options through Invitae are particularly informative and generally affordable.
There is even a genetic counseling process available to individuals who’d like to order this testing-
https://www.invitae.com/en - all the options
https://www.invitae.com/en/staying-healthy - Staying healthy (mainly cancer and cardio)
https://www.invitae.com/en/pregnancy- Reproductive/Carrier screening
23andMe is fun information…. Some of the carrier screening is done on their platforms however, they do not
do full gene sequencing, but rather targeted mutation analysis. Any findings on 23andMe need to be
confirmed by clinical and diagnostic lab.
Advice from Deena Whaba the Genetics Counselor at Saint Anthony's

75. https://www.genome.gov/event-calendar/Bold-Predictions-for-Human-Genomics-by-2030
#6 , Genomic Testing will become commonplace like a standard medical test
#8, A person’s complete genome will be available on their smart phone in a user friendly format

76. https://www.pancan.org/facing-pancreatic-cancer/about-
pancreatic-cancer/risk-factors/genetic-hereditary/

77. In some cancers like
pancreas cancer, the role
of family history and
genetics may be huge

78. So far (2020) have
only identified the
relevant gene
mutation in less
than 20% of the
cases

79. Pancreas Cancer

80. High risk genes
are rare, lower
risk genes are
more common

81. Huge individual variation of little
or unknown significance

82. Current Status of Pancreas Cancer Genes