Identifying hereditary cacner predisposition syndrom

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Hereditary Cancer
4 April 2022

2. Outline
• Introducing
• Hereditary Cacner
• BRCA 1/2
• When and Who Need Genetic Screening
• What Nex Option If Positif Result
• Conclussion

3. Introducing

4. Kanker Di Indonesia

5. Genetic Information And Cancer
• Genetic testing and analysis are revolutionizing health care, including
cancer diagnosis and treatment.
• Probing a tumor’s genetic material can help doctors better
understand, monitor, and treat their patients with a much more
precise and individualized approach.
• To get there, scientists need to learn much more about how to
interpret the genetics of cancer. Bioinformatics will be “fundamental
to all cancer care and treatment going forward”
Dr. Lynn Fink, PhD

7. The Genetics of Cancer
Mutasi Somatik
• Mutasi dapat terjadi secara spontan pada sebagian
besar jenis sel setiap saat.
• Mutasi yang terjadi pada sel somatik (semua sel tidak
termasuk sel sperma dan sel telur) baik pada masa
perkembangan maupun pada masa dewasa
• tidak akan diwariskan kepada generasi berikutnya.
Mutasi pada sel ini hanya akan diteruskan ke sel anak
yang membelah sebagai bagian dari pembelahan sel
normal yang terjadi pada jaringan dan organ dalam
tubuh.
Mutasi Germ-Line
• Mutasi yang akan diteruskan ke keturunan
organisme,
• Terjadi pada gamet induk (telur dan sperma, juga
disebut sebagai garis germinal).
• Mutasi juga dapat terjadi selama perkembangan
sperma dan sel telur, menghasilkan mutasi spontan
yang diteruskan ke generasi berikutnya.
Cancer is a genetic disease—that is, cancer is
caused by certain changes to genes that control the
way our cells function, especially how they grow and
divide.

8. Type of Mutasi/ Variant
A concerted effort is being made within the genetics community to shift
terminology used to describe genetic variation. The shift is to use the term
“variant” rather than the term “mutation” to describe a difference that exists
between the person or group being studied and the reference sequence,
particularly for differences that exist in the germline.

9. Variant in Cancer
Adapted from Richards S, Aziz N, Bale S, et al.: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the
American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17 (5): 405-24, 2015.
Type of Variant Description
Pathogenic Directly contributes to the development of disease. Additional evidence is
not expected to alter the classification of this variant. Note: Not all
pathogenic variants are fully penetrant.
Likely pathogenic Very likely to contribute to the development of disease, but scientific
evidence is currently insufficient to prove this conclusively.
Uncertain
significance
There is not enough information at this time to support a more definitive
classification of this variant.
Likely benign Not expected to have a major effect on disease, but the scientific evidence
is currently insufficient to prove this conclusively.
Benign Does not cause disease. Additional evidence is not expected to alter
classification of this variant.

10. TIPE KANKER
KANKER
HEREDITER
KANKER FAMILIAL
Ayah sehat Ibu sehat
Anak laki2
sehat
Anak
perempuan
sehat
Anak laki2
sehat
Anak
perempuan
terkena kanker
Anak laki2 terkena
kanker
Anak
perempuan
sehat
Anak laki2
sehat
Anak
perempuan
sehat
KANKER
SPORADIK
Ayah sehat Ibu sehat
Anak laki2
sehat
Anak
perempuan
sehat
Anak laki2
sehat
Anak
perempuan
terkena
kanker
Anak laki2
sehat
Anak
perempuan
sehat
Anak laki2
sehat
Anak
perempuan
sehat
Ayah terkena
kanker Ibu sehat
Anak laki2 terkena
kanker
Anak
perempuan
sehat
Anak laki2
sehat
Anak
perempuan
terkena kanker
Anak laki2
terkena kanker
Anak
perempuan
sehat
Anak laki2
sehat
Anak perempuan
sehat
https://myriadgenetics.eu/patients/hereditary-cancer/genetic-testing/population-at-risk/

11. TIPE KANKER
• Sporadic Cancer
• Various factors
• Age, environmental, lifestyle
• Familial Cancer
• Combination
environment/lifestyle factor and
genetic factor
• Hereditary Cancer
• Errors/faults in gene

12. This presentation has been prepared specifically by Prodia. The content of this presentation may not be used,
duplicated or transmitted in any form without the written consent from Prodia. All rights reserved.
Hereditary Cancer

13. This presentation has been prepared specifically by Prodia. The content of this presentation may not be used,
duplicated or transmitted in any form without the written consent from Prodia. All rights reserved.
Genetic Predisposition to Disease
Mendelian disorders are generally associated with variants in a
single gene or family of genes, which are typically identified
through linkage studies involving families affected with a
specific disorder.
Variants associated with common complex disorders are
typically identified through large-scale genome-wide
association involving cases compared to unaffected controls.
Most such variants are intergenic rather than in the coding DNA
and individually exert only a slight influence on risk.
A polygenic risk score is the quantification of the cumulative
effect of a number of genetic variants which individually have a
small effect on susceptibility to disease of interest.
Variants associated with cancer are associated with different
risks, depending on patient age/gender, the type of variant, the
gene/part of the gene in which they are located, and other
coinherited genetic modifiers. The risk of cancer may also be
modified further by lifestyle/environmental factors.

14. Genetic Predisposition to Disease
• All cancers develop as a result of pathogenic or likely pathogenic (P/LP) variants in certain
genes, such as those involved in the regulation of cell growth and/or DNA repair,
although not all of these P/LP variants are inherited from a parent.
• For example, sporadic P/LP variants can occur in somatic/tumor cells only, and de novo P/LP
variants can occur for the first time in a germ cell (ie, egg or sperm) or in the fertilized egg itself
during early embryogenesis. However, family studies have long documented an increased risk
for several forms of cancer among first-degree relatives (ie, parents, siblings, children) and
second-degree relatives (ie, grandparents, aunts or uncles, grandchildren, nieces or nephews)
of affected individuals.
• These individuals may have an increased susceptibility to cancer as the result of one or more
P/LP variants present in parental germline cells; cancers developing in these individuals may
be classified as hereditary or familial cancers.

15. Hereditary Cancer
• Hereditary cancers are often characterized by P/LP variants associated with increased risk
for certain cancers (ie, a high-penetrance phenotype) and transmission to offspring
through the mother and/or father.
• They often have an early age of onset and exhibit an autosomal dominant inheritance
pattern (ie, occur when the individual has a P/LP variant in only one copy of a gene).
Familial cancers share some but not all features of hereditary cancers.
• For example, although familial breast cancers occur in a given family more frequently than
in the general population, they generally do not exhibit the inheritance patterns or onset
age consistent with hereditary cancers. Familial cancers may be associated with chance
clustering of sporadic cancer cases within families, genetic variation in lower penetrance
genes, a shared environment, or combinations of these factors

16. Inherited and acquired mutations
• Orang mewarisi satu salinan dari setiap gen dari ibu mereka dan satu salinan dari ayah mereka.
Kadang-kadang, orang tua dapat mewariskan gen dengan kerusakan yang disebut "mutasi"
kepada anak-anak mereka. Anak-anak dapat mewariskan mutasi yang sama kepada masing-
masing anak mereka. Jika Anda dilahirkan dengan mutasi gen yang berasal dari ibu atau ayah
Anda, berartimemiliki "mutasi gen yang diturunkan".
• Mutasi gen yang diturunkan tidak selalu menyebabkan kanker. Jika anka mewarisi gen yang rusak
dari ayah, masih memiliki salinan normal dari gen yang sama dari ibu. Begitu senaliknya
• Mutasi "Acquired" adalah kerusakan pada gen yang terjadi setelah seseorang lahir. Mereka
disebabkan oleh "keausan" pada gen dari waktu ke waktu. Penuaan, paparan hormon, racun
lingkungan dan virus tertentu dapat menyebabkan mutasi gen. Kerusakan yang menumpuk di sel
dapat menyebabkan kanker.
• Orang dengan mutasi bawaan dilahirkan dengan satu gen yang sudah rusak di semua sel dalam
tubuh mereka. Ini berarti lebih sedikit langkah yang diperlukan sel mereka untuk
mengembangkan kanker.

17. Sporadic vs Herediter Cancer
Contoh Pemeriksaan: CArisk 2.0 Contoh Pemeriksaan: Hereditary Cancer Risk
Dan BRCA 1/2 Germline

18. 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 or DNA repair
genes include BRCA1, BRCA2, and p53 or TP53.
• Mutations in DNA repair genes may be
inherited or acquired. Lynch syndrome is an
example of the inherited kind. BRCA1, BRCA2,
and p53 mutations and their associated
syndromes are also inherited.
• 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, a specialized protein that controls
cancer growth and spread. It is found in
some cancer cells. For example, breast and
ovarian cancer cells.
• The RAS family of genes, which makes
proteins involved in cell communication
pathways, cell growth, and cell death.

19. Cells have tools to repair DNA damage. If it cannot be repaired, the body has ways to remove the damaged cell so
that it cannot divide and create more damaged cells. This system isn't always perfect, and DNA damage and gene
mutations can build up in cells. Over time, this can lead to cancer.

20. Why Is Genetic Testing Important in Finding
Cancer Risk?
Genetic testing may help:
• Predict your risk of a particular disease
• A test will clearly show a specific genetic change.
• Find if you have genes that may pass increased cancer risk to your
children
• A personal or family history suggests a genetic cause of cancer.
• Provide information to guide health care provider
• The results will help with diagnosis or management of a condition.
• For example, steps to lower risk: Steps may include surgery, medication,
frequent screening, or lifestyle changes.

21. Risk factors for hereditary cancer
A hereditary cancer is any cancer caused by an inherited gene mutation. An
inherited gene means it is passed from parent to child within a family. The
following factors suggest a possible increased risk for hereditary cancer:
• Family history of cancer. Having 3 or more relatives on the same side of the
family with the same or related forms of cancer.
• Cancer at an early age. Having 2 or more relatives diagnosed with cancer at an
early age. This factor may differ depending on the type of cancer.
• Multiple cancers. When one relative develops 2 or more types of cancer.
• Rare cancers. Some types of cancer, such as ovarian cancer, adrenocortical
cancer, or sarcoma, are linked to inherited genetic mutations.

22. BRCA 1/2

23. BRCA1/2
• BRCA1 dan BRCA2 adalah dua gen penting yang menjadi
predisposisi utama pada hereditary breast and ovarian cancer
(HBOC).
• Varian germline pada dua gen yang bersifat highly penetrance ini
akan meningkatkan risiko untuk mendapatkan tumor ini sebanyak
50-80 %, dan juga berhubungan dengan onset penyakit yang lebih
dini.
• Pada populasi umum, varian pathogenic BRCA1 terjadi pada sekitar
1 dari 300-500 wanita, dan BRCA2 terjadi pada 1 dari 800 wanita.
• Sementara pada populasi Ashkenazi-Jewish memiliki frekuensi
carrier sebesar 2-5 % untuk 3 founder mutation dari gen BRCA1 (-
185delAG, 5382insC) dan BRCA2 (6174delT).
• Mutasi BRCA1/2 ditemukan pada 5-10 % kasus breast cancer dan 15
% kasus ovarian cancer, terutama pada keluarga dengan beberapa
individu yang terkena selama beberapa generasi.
US Preventive Services Task Force et al. “Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force
Recommendation Statement.” JAMA vol. 322,7 (2019): 652-665. doi:10.1001/jama.2019.10987

24. Summary BRCA 1/2 Gene
Hatano Y, Tamada M, Matsuo M and Hara A (2020) Molecular Trajectory of BRCA1 and BRCA2 Mutations. Front.
Oncol. 10:361. doi: 10.3389/fonc.2020.00361

25. BRCA gene 1/2
• Cancer predisposition genes, BRCA1 and BRCA2, were first discovered in the genetic study
on familial breast cancer. Linkage analyses with DNA polymorphic markers were detecting the
causal relationships between certain genetic diseases and specific genomic loci.
• As a common function between BRCA1 and BRCA2, HR is an essential DNA repair system
that enables the error-free recovery of double strand breaks (DSBs).
• DSBs are the most severe DNA damage, the accumulation of which results in genetic
translocation and cell death.
• In the condition of homologous recombination deficiency (HRD) by BRCA dysfunction,
restoration of DSBs depends on an error-prone repair machinery, known as non-homologous
end joining (NHEJ).
• Such an HRD, also called genomic instability, is advantageous for the progression of BRCA-
associated cancer to effectively gain sequence and structural variance, especially in the early
phase
Zhang H, Tombline G, Weber BL. BRCA1, BRCA2, and DNA damage response: collision or
collusion? Cell. (1998) 92:433–6. doi: 10.1016/S0092-8674(00)80936-8

26. Characteristics of Cancer With BRCA
Dysfunctions
• The recent TCGA study addressed the molecular classification of gynecologic and breast
cancers, and acknowledged the existence of a subset of cancers with BRCA-associated
mutational signatures.
• In breast cancer, BRCA1-mutated carcinoma is significantly associated with the basal-like
subtype that exhibits negative expression of the estrogen receptor (ER), progesterone receptor
(PGR), and ERBB2/HER2.
• BRCA1-mutated and basal-like breast cancer are high grade carcinomas with frequent TP53
mutations , indicating that coexisting BRCA1 and TP53 mutations facilitate breast cancer
progression.
• In the breast surgical specimens of BRCA-carriers, the dedicated histological examination
revealed a distinctive pathologic condition known as “hyaline fibrous involution”.
• Ovarian cancer among BRCA-carriers tends to be the most frequent histological type; it is a
high-grade serous carcinoma (HGSC)
• Berger AC, Korkut A, Kanchi RS, Hegde AM, Lenoir W, Liu W, et al. A comprehensive pan-cancer molecular study of gynecologic and breast
cancers. Cancer Cell. (2018) 33:690–705. doi: 10.1016/j.ccell.2018.03.014
• Hatano Y, Tamada M, Matsuo M and Hara A (2020) Molecular Trajectory of BRCA1 and BRCA2 Mutations. Front. Oncol. 10:361. doi:
10.3389/fonc.2020.00361

27. BRCA 1 and BRCA 2 associated breast cancer
Hodgson A, Turashvili G. Front Oncol. 2020;10:531790. Published 2020
Sep 29. doi:10.3389/fonc.2020.531790

28. Characteristics of Cancer With BRCA
Dysfunctions
• In addition to breast and ovarian cancers, pancreatic and prostate cancers rarely harbor BRCA
mutations and BRCA-associated signatures
• The clinical sequence studies reveal that the germline BRCA2 mutation is detected in ~5% of
metastatic prostate carcinoma cases.
• Pancreatic cancer also harbors BRCA2 mutations. Of the common types of cancer, including
pancreatic ductal adenocarcinoma (PDAC) ~4 % and neuroendocrine tumors (PanNET) 1%
possess germline BRCA2 mutations.
• These findings suggest that mutated BRCA2-carriers should exercise caution regarding the
development of extra-mammary and uterine adnexal cancers.
• Berger AC, Korkut A, Kanchi RS, Hegde AM, Lenoir W, Liu W, et al. A comprehensive pan-cancer molecular study of gynecologic and breast
cancers. Cancer Cell. (2018) 33:690–705. doi: 10.1016/j.ccell.2018.03.014
• Hatano Y, Tamada M, Matsuo M and Hara A (2020) Molecular Trajectory of BRCA1 and BRCA2 Mutations. Front. Oncol. 10:361. doi:
10.3389/fonc.2020.00361

29. PARP Inhibitor
Astra Zeneca : LYNPARZA® (Olaparib)
Glaxo Smith Kline (GSK) : ZEJULA® (Niraparib) Pfizer
: TALZENA® (Talazoparib)
Untuk menentukan penggunaan terapi yang paling
sesuai dengan pasien.
• Karena gen BRCA1 dan BRCA2 terlibat dalam
perbaikan DNA, tumor dengan perubahan pada
salah satu gen sangat sensitif terhadap agen
antikanker yang bekerja dengan merusak DNA,
seperti cisplatin.
• Golongan obat yang disebut PARP inhibitor
memblokir perbaikan kerusakan DNA untuk
menghentikan pertumbuhan sel kanker yang
memiliki varian BRCA1 atau BRCA2 yang
berbahaya.

30. Hereditary Breast Cancer
Study Shin HC et al (2020), Found: From 496
breast cancer patients of Asian ethnicity with
clinical features of HBOC using NGS-based multi-
gene panel testing.
• 95 patients (19.2%) were found to carry 48
deleterious germline mutations in 16 cancer
susceptibility genes. Of these 95 patients:
• 60 patients (63.2%) had
BRCA1/2mutations,
• 38 patients (40.0%) had non-BRCA1/2
mutations,
• 3 patients (3.2%) had both BRCA1/2 and
non-BRCA1/2 mutations.
Shin HC, Lee HB, Yoo TK, et al. . Cancer Res Treat. 2020;52(3):697-713. doi:10.4143/crt.2019.559

31. Multi Gene Testing From NCCN, Guidelines, Version 2.2021 -
Genetic Familial High Risk Assesment: Breast, Ovarian, and
Pancreatic.
NCCN Guidelines,
Genetic/Familial High
Risk Assessment: Breast,
Ovarian, and Pancreatic,
Version 2.2022

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duplicated or transmitted in any form without the written consent from Prodia. All rights reserved.
Application of Hereditary Cancer
Testing

33. Features of
hereditary
cancer
Pada pasien individu:
• Beberapa tumor primer pada organ yang sama.
• Beberapa tumor primer di organ yang berbeda.
• Tumor primer bilateral pada organ
berpasangan.
• Multifokalitas dalam satu organ (misalnya,
beberapa tumor di payudara yang sama, yang
semuanya berasal dari satu tumor asli).
• Usia yang lebih muda dari biasanya saat
diagnosis tumor.
• Tumor dengan histologi langka.
• Tumor yang terjadi pada jenis kelamin biasanya
tidak terpengaruh (misalnya, kanker payudara
pada pria).
• Tumor yang terkait dengan sifat genetik
lainnya.
• Tumor yang berhubungan dengan cacat
bawaan.
• Tumor yang terkait dengan lesi prekursor yang
diturunkan.
• Tumor yang terkait dengan penyakit langka
lainnya.
• Tumor yang terkait dengan lesi kulit yang
diketahui terkait dengan gangguan kerentanan
kanker (misalnya, genodermatosis).
Pada keluarga pasien:
• Satu kerabat tingkat pertama dengan
tumor yang sama atau terkait dan
salah satu ciri individu.
• Dua atau lebih kerabat tingkat
pertama dengan tumor di tempat
yang sama.
• Dua atau lebih kerabat tingkat
pertama dengan jenis tumor yang
termasuk dalam sindrom kanker
familial yang diketahui.
• Dua atau lebih kerabat tingkat
pertama dengan tumor langka.
• Tiga atau lebih kerabat dalam dua
generasi dengan tumor di tempat
yang sama atau tempat yang terkait
secara etiologis.

35. Siapa saja yang termasuk keluarga pasien?
Kriteria untuk keluarga psien dikategorikan menjadi:
1. First-Degree Relatives (1): Orang tua, Saudara kandung,
2. Second-degree relatives (2): Kakek-nenek, Bibi, Paman, Cucu, saudara tiri (satu
bapak/ satu ibu)
3. third-degree relatives (3) : Buyut, Cicit, Sepupu Pertama, paman buyut, bibi buyut
Male
Female

36. What Next?
• The benefit of BRCA1/2 testing comes from linking test results to interventions to reduce
cancer risk.
• For women who are found to carry a mutation, the most dramatic–and also most effective–risk
reduction intervention is prophylactic surgery, which Jolie chose.
• Prophylactic mastectomy reduces the risk of breast cancer by over 90%. Prophylactic
oophorectomy has a similar effect on the risk of ovarian cancer and also reduces the risk of
breast cancer.
• For women who do not undergo prophylactic surgery, yearly screening with mammography
and breast magnetic resonance imaging and biannual pelvic ultrasonography with cancer
antigen 125 (CA-125) testing is often used, although definitive evidence of a mortality benefit is
lacking.
• The oral medications tamoxifen and raloxifene reduce the risk of developing breast cancer and
are included in current recommendations for risk management among women who carry
mutations.
McCarthy AM, Armstrong K. The role of testing for BRCA1 and BRCA2
mutations in cancer prevention. JAMA Intern Med. 2014;174(7):1023-
1024. doi:10.1001/jamainternmed.2014.1322

37. From NCCN

38. How can a person who has inherited
a harmful BRCA1 or BRCA2 gene
variant reduce their risk of cancer?
• Enhanced screening
• Breast awareness starting at age 18
• Clinical breast exam 2X per year beginning at age 25
• Yearly MRI or mammogram (Age 25-29 years)
• Yearly MRI and mammogram (Age 30-75 years)
• Risk-reducing surgery
• Risk-reducing bilateral mastectomy 85-100% reduction in
breast cancer risk
• Risk-reducing oophorectomy or bilateral salpingo-
oophorectomy (BSO)
• 69-100% reduction in ovarian cancer risk
• 37-100% reduction in breast cancer risk
• Chemoprevention
• Tamoxifen or raloxifene
Source: National Comprehensive Cancer Network. NCCN Guidelines Version 2.2022 Genetics/Familial High-Risk
Assessment: Breast and Ovarian. BRCA-A.

39. Prevention Strategies (NCCN)
Dalam Guideline NCCN Disertakan opsi untuk menurunkan risiko yang sebagian adalah upaya untuk deteksi
dini (skrining yang diperketat)

40. This presentation has been prepared specifically by Prodia. The content of this presentation may not be used,
duplicated or transmitted in any form without the written consent from Prodia. All rights reserved.
Targeted Therapy
PARP Inhibitor
Untuk menentukan penggunaan terapi yang paling
sesuai dengan pasien.
• Karena gen BRCA1 dan BRCA2 terlibat dalam
perbaikan DNA, tumor dengan perubahan pada
salah satu gen sangat sensitif terhadap agen
antikanker yang bekerja dengan merusak DNA,
seperti cisplatin.
• Golongan obat yang disebut PARP inhibitor
memblokir perbaikan kerusakan DNA untuk
menghentikan pertumbuhan sel kanker yang
memiliki varian BRCA1 atau BRCA2 yang
berbahaya.