This document discusses the genetics and epigenetics of breast and colorectal cancer. It outlines several high-penetrance genes associated with increased risk of breast cancer such as BRCA1 and BRCA2. It also discusses moderate and low-penetrance genes and their roles in DNA damage response pathways. For colorectal cancer, it describes hereditary syndromes like Lynch syndrome caused by mutations in mismatch repair genes and familial adenomatous polyposis caused by APC gene mutations. It concludes by briefly mentioning the role of epigenetics in cancer development.
4. Risk factors
Family history with breast cancer
Early menstruation before age 12
Late menopause after age 55
BEYONDTHESHOCK.COM 4
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with risk factors witout risk factors
8. high-penetrance genes
RAKHA EA, REIS-FILHO JS, ELLIS IO. BASAL-LIKE BREAST CANCER: A CRITICAL REVIEW. J CLIN 8
estrogen receptor (ER) rogesterone receptor (PR) r Her2/neu
triple-negative tumor
9. high-penetrance genes
WOOSTER R, NEUHAUSEN SL, MANGION J ET AL. LOCALIZATION OF A BREAST CANCER 9
BRCA2-related tumors more closely resemble sporadic tumors
10. high-penetrance genes
DOMCHEK SM, TANG J, STOPFER J ET AL. BIALLELIC DELETERIOUS BRCA1 MUTATIONS IN A WOMAN
WITH EARLY-ONSET OVARIAN CANCER. CANCER DISCOV 2013; 3: 399–405. 10
clinical picture of Fanconi anemia
type D1 and greatly increase the
risk of childhood cancers.
11. high-penetrance genes
KING MC, MARKS JH, MANDELL JB, NEW YORK BREAST CANCER STUDY GROUP. BREAST AND OVARIAN CANCER RISKS DUE TO INHERITED MUTATIONS IN BRCA1 AND BRCA2. SCIENCE 2003; 302: 643–646.
LINDOR NM, MCMASTER ML, LINDOR CJ ET AL. CONCISE HANDBOOK OF FAMILIAL CANCER SUSCEPTIBILITY SYNDROMES—SECOND EDITION. J NATL CANCER INST MONOGR 2008; 1–93. 11
OR a lifetime risk of breast cancer of 50%–
85%
12. high-penetrance genes
LIEDE A, KARLAN BY, NAROD SA. CANCER RISKS FOR MALE CARRIERS OF GERMLINE MUTATIONS IN BRCA1 OR BRCA2: A REVIEW OF THE LITERATURE. J CLIN ONCOL 2004; 22: 735–742. 12
Male carries of BRCA1 have an increased risk of breast cancer,
though to a lesser degree than carriers of BRCA2 who have an
estimated 5%–10% lifetime risk
13. high-penetrance genes
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PIP2
P PIP3
PTEN
AKT
CYCLIN D1
GSK3B
Forkhead
mTOR
FitzGerald MG, Marsh DJ, Wahrer D et al. Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene 1998; 17: 727–731.
Tan MH, Mester JL, Ngeow J et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012; 18: 400–407.
14. Other high-penetrance genes
Gene Syndrome Breast cancer incidence
TP53 Li-Fraumeni Syndrome 25% by age 74
CDH1 Hereditary Diffuse Gastric Cancer 39% lifetime risk of lobular breast
cancer
STK11 Peutz-Jeghers Syndrome 32% by age 60
S. SHIOVITZ GENETICS OF BREAST CANCER: A TOPIC IN EVOLUTION 14
15. moderate-penetrance genes
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CHEK2: Protein kinase involved in cell cycle regulation at G2. Rapidly
phosphorylated in response to DNA damage. Activated CHEK2 stabilizes p53
and interacts with BRCA1
16. 16
Double strand break
CHEK2 CHEK2
P
ATM
Activates proteins like CDC25
Stabilization of p53
Meijers-Heijboer H, van den Ouweland A, Klijn J et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in
noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002; 31: 55–59.
17. KEGG PATHWAY 17
• CHEK2: Protein kinase involved in cell cycle
regulation at G2. Rapidly phosphorylated in response
to DNA damage. Activated CHEK2 stabilizes p53 and
interacts with BRCA1
• BRIP1 (BACH1): Interacts with the BRCA1 C-
Terminus (BRCT) domain of BRCA1
• ATM: Protein kinase involved in monitoring and
repair of dsDNA and regulation of BRCA1 and
CHEK2
• PALB2: Associates with BRCA2. Involved in nuclear
localization and stability
moderate-penetrance genes
18. low-penetrance alleles
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NPs are found in both genes and intergenic regions; variation in the latter of these
can indicate variation in gene regulatory elements. These studies require thousands
of cases and controls to have sufficient power to appreciate a change in risk, as
individuals alleles may be relatively common and even found in a majority of the
population
A small number of polymorphisms in known breast cancerassociated genes have
been associated with an increased risk of breast cancer
19. low-penetrance alleles
Evaluation for low-penetrance alleles is not currently part of standard clinical evaluation for
breast cancer. Management of individuals found to carry these variants, as with moderate-
penetrance genes, should be based on their estimated risk as calculated by the previously
described validated risk assessment models.
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21. Colorectal cancer(CRC)
Both hereditary and sporadic CRCs are
genetically driven diseases. Hereditary CRC
syndromes are caused by germline mutations
and sporadic CRC is driven by alterations in DNA
structure (mutations) or function (epigenetics).
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22. Molecular pathways to colorectal cancer
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JANNE PA, MAYER RJ. CHEMOPREVENTION OF COLORECTAL CANCER. N ENGL J MED
2000;342(26):1961.
23. Molecular pathways to colorectal cancer
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JANNE PA, MAYER RJ. CHEMOPREVENTION OF COLORECTAL CANCER. N ENGL J MED
2000;342(26):1961.
Hereditary non-polyposis colorectal
cancer (HNPCC)Lynch syndrome:
• Most common inherited colon cancer
• Germline mutation in one of several
mismatch repair(MMR) genes
• Autosomal dominant
HNPCC defects in DNA MMR genes leads
to microsatellite instability
(Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer:
the syndrome, the genes, and historical perspectives. J Natl Cancer
Inst 1995;87:1114-1125.)
24. Molecular pathways to colorectal cancer
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JANNE PA, MAYER RJ. CHEMOPREVENTION OF COLORECTAL CANCER. N ENGL J MED
2000;342(26):1961.
25. CRC risk factors
1. a strong family history of CRC and/or polyps;
2. multiple primary cancers in a patient with CRC;
3. the existence of other cancers within the kindred consistent with
known syndromes causing an inherited risk of CRC, such as
endometrial cancer
4. early age at diagnosis of CRC.
25HTTPS://WWW.CANCER.GOV/TYPES/COLORECTAL/HP/COLORECTAL-GENETICS-PDQ
26. Familial adenomatous polyposis (FAP)
FAP is inherited in an autosomal dominant matter by a germline mutation in the adenomatous
polyposis coli (APC) gene.
Most patients have a family history of the disease, however approximately 25% emerge as ‘de
novo’ gene mutations in the APC gene
Mutations of APC such as
Insertion
Deletion
Non sense mutation
26Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994;3:121-125
result in a trunctated APC protein
28. MUTYH-associated polyposis (MAP)
A subset of patients with clinical FAP and AFAP, without a strong
multigenerational family history, does not have a detectable APC gene
mutation. In these patients an autosomal recessive disorder, MAP, is
frequently seen. This condition is caused by a biallelic germline mutation in
the base-excisionrepair (BER) gene MUTYH. About 30% of patients will
also develop polyps in the upper gastrointestinal tract, but no extra-intestinal
manifestations are seen . Patients have an 80% risk of developing CRC and
the mean age of diagnosis is between 40 and 60 years old. When diagnosed,
the management is similar to those with FAP.
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29. Peutz-Jeghers syndrome (PJS)
Very rare
Autosomal dominant
Characterized by multiple hamartomatous polyps of the gastrointestinal tract
Patients with PJS have a germline mutation of the serine threonine kinase 11
(STK-11), a tumor suppressor gene. Adults with PJS not only have a high risk of
developing gastrointestinal cancer, but also non-gastrointestinal cancers, especially
breast cancer.
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