Download Hereditary Breast Cancer

Hereditary Breast Cancer: Genes,
Associated Syndromes and Testing Options
TESTING SUMMARY
AUTHORS
Adrian Vilalta, Ph.D. - Sr. Director, Genetics
Aditi Chawla, Ph.D. - Scientific Lead, Genetics
Russell Chan, Ph.D. - Sr. Scientist, Genetics
Ryan Friese, Ph.D. - Sr. Scientist, Genetics
Svetlana Gramatikova, Ph.D. - Sr. Scientist, Genetics
Dan Zhu, Ph.D. - Sr. Scientist, Genetics
HBOC Testing / White Paper
Hereditary Breast Cancer:
Genes, Associated Syndromes and Testing Options
Introduction
Cancer can occur as a result of various factors, including inherited and acquired genetic mutations, diet,
lifestyle choices and age. It has long been recognized that cancer risk is higher in some families and ethnic
groups as compared to the population at large, suggesting a genetic component to the overall breast cancer
risk. Studies of high risk breast and ovarian cancer families led to the discovery of the BRCA1 and BRCA2 genes
in the mid 1990s. BRCA1 and BRCA2 are the two genes with the strongest association with increased risk for
breast cancer accounting for approximately 5-7% of all breast cancer cases [1]. In addition, mutations in BRCA1
and BRCA2 greatly increase the risk for ovarian cancer [2]; mutations in BRCA1/2 lead to the so called hereditary
breast and ovarian cancer syndrome (HBOC). Although BRCA1 and BRCA2 are the most recognized genes
with an association with breast cancer, mutations in other genes need to be considered in non-BRCA1/2 high
risk families. Most notably amongst these are genes previously associated with well-studied genetic disease
syndromes, i.e., PTEN (Cowden), TP53 (Li-Fraumeni), CDH1 (hereditary diffuse gastric cancer), and STK11(PeutzJehgers) [3]. Remarkably, a recent (August, 2014), large study of hereditary breast cancer patients established
the PALB2 gene as a key contributor to hereditary breast cancer [4-6]. Given the complexities of testing for a
predisposition for breast cancer, Pathway Genomics offers a suite of testing options to best accommodate
the personal and family history of each patient. These testing options include single mutation testing, an
Ashkenazi Jewish mutation panel, a BRCA1/2 test, and, importantly, a high-risk breast cancer panel that
includes the PALB2 gene. To further add to the flexibility of testing, several reflex testing options are also
available.
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Breast and Ovarian Cancer
Breast cancer is defined as a malignant tumor in the breast caused by uncontrolled division of abnormal cells.
The disease occurs in men and in women, though male breast cancer is rare. Women in the general population
have a 12.3% lifetime risk of breast cancer; 1 in 8 women will develop the disease [7]. In contrast, men have a
lifetime risk of 0.13%, or about 1 in 1,000 [8].
Ovarian cancer is a malignancy in the ovaries caused by uncontrolled division of abnormal cells. The lifetime risk
of developing ovarian cancer in the general population is 1.4%, or about 1 in 71 [7].
Hereditary Breast and Ovarian Cancer (HBOC)
DNA changes (mutations) in the BRCA1 and BRCA2 genes can lead to significantly increased lifetime risks for
breast and ovarian cancer (Figure 1). Mutations in BRCA1 and BRCA2 lead to a condition known as hereditary
breast and ovarian cancer syndrome or HBOC. HBOC accounts for 5-7% of breast cancer cases [1] and 8–13%
of epithelial ovarian cancer cases [2]; however, BRCA1 and BRCA2 mutations account for up to 80% of breast
and ovarian cancer in families with multiple cases of either disease [3, 9, 10]. Schematic representations of family
pedigrees diagnosed with HBOC are depicted in figure 2. Importantly, mutations in either BRCA1 or BRCA2 can
be inherited from the maternal as well as the paternal side of the family. HBOC syndrome is also associated with
increased risk of other types of cancer, including but not limited to fallopian tube [11-13], peritoneal [14-16], pancreatic
[17-19]
, prostate [18, 20-22], and male breast cancers [23, 24].
Lifetime Risk of Cancer (%)
0 20406080
0 1020304050
Breast
Ovarian
General Population
BRCA1 - mutation
BRCA2 - mutation
Figure 1: The cumulative lifetime risk to age 70 years for breast or ovarian cancer. [22]
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BRCA1
BRCA2
Ovarian, dx 49
Breast, dx 42
Prostate, dx 55
Ovarian, dx 53
Breast, dx 45
Pancreatic, dx 55
Breast, dx 38
Ovarian, dx 58
Breast, dx 52
Figure 2: Schematic representations of family pedigrees diagnosed with pathogenic mutations in either the BRCA1 or BRCA2 gene.
Interpretation guide: (1) circles represent females while squares represent males, (2) shading indicates an affected individual, (3) a diagonal
line indicates the individual is deceased and (4) each level indicates a generation. Age of diagnosis is indicated as “dx”. Adapted from [25].
BRCA1/2 and Ethnicity
Prevalence of BRCA1/2 in the general population has been reported to be approximately 1/400 [22]. Large population
studies [8, 26] of breast cancer survivors under the age of 65 revealed strong ethnic differences in the prevalence of
pathogenic mutations in BRCA1 or BRCA2 gene (Table 1).
BRCA1
BRCA2
Ashkenazi Jewish
8.3-10.2%
1.1%
Hispanic
3.5%
Data not available
Caucasian (non-Ashkenazi Jewish)
2.2-2.4%
2.2%
African-American
1.3-1.4%
2.6%
Asian-American
0.5%
Data not available
Table 1: Prevalence of BRCA1 and BRCA2 mutations in women with breast cancer by ethnic group within U.S. Adapted from [8, 26].
BRCA1/2 Ashkenazi Jewish founder mutations
Inherited predisposition for breast and ovarian cancer among people of Ashkenazi (Central and Eastern European)
Jewish ethnic background has long been recognized. Approximately one in forty Ashkenazim carry one of three
founder mutations in BRCA1 (185delAG or 5382insC) or BRCA2 (6174delT) [27-29]. Recent studies show that 29%
of Jewish women with ovarian cancer carry one of these three founder mutations [30]. Data from a recent study [31]
indicate that a BRCA1/2 mutation was detected in 44% of a group of 220 high risk Ashkenazi breast cancer families.
This number increased to 73% if ovarian cancer was present in the kindred.
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BRCA1/2 founder mutations in other ethnic groups
Although, as discussed above, the prevalence of founder mutations in BRCA1 and BRCA2 is higher in Ashkenazim
compared to the general population, there are also some well-characterized BRCA1/2 founder mutations in other
ethnic groups. For example, in the Mexican population, two mutations in BRCA1 represent about 45% of the
observed BRCA1/2 mutations (185delAG and ex9-12 del) [32, 33] in that population. A partial list of well-documented
founder mutations is presented in Table 2.
Gene
BRCA2
BRCA2
BRCA1
BRCA1
BRCA1
BRCA1
BRCA1
BRCA1
BRCA2
BRCA2
BRCA1
BRCA1
Mutation
4265delCT
c.9345+1G>A
3600del11
Y978X
5083del19
c.188T>A
185delAG
Exon9-12del
3492insT
c.145G>T
c.1556delA
c.3048_3052dupTGAGA
Ethnicity
Filipino
Finns
French
Iranian Jews
Italian
Japanese
Mexican
Mexican
Mexican
Mexican
Norway
Swedish/Danish
Reference
[34]
[35]
[36]
[37]
[38, 39]
[40]
[32, 33]
[32, 33]
[32, 33]
[32, 33]
[41]
[42]
Table 1: Partial list of BRCA1/2 founder mutations by ethnic group.
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Other High Penetrance Genes
Cases of familial breast cancer not related to BRCA1 or BRCA2 are thought to be caused by other genes, each one
accounting for a fraction of the total cases of familial breast cancer. Some of these additional high risk susceptibility
genes include CDH1, PALB2, PTEN, STK11, and TP53 [3]. As can be appreciated from Figure 3, extremely rare, highpenetrance mutations in a handful of genes are responsible for the largest contribution to breast cancer risk.
BreastTrueTM High Risk Panel
20.0
Risk Estimate (OR)
10.0
TP53
BRCA1
STK11
PALB2
PTEN
BRCA2
CDH1
5.0
2.0
NBN
RAD5Q
BLM
1.5
ATM
CHEK2
CCDN1
CDKN2A
TOX3
MDM4
1.1
TERT
0.01 0.11.010.020.030.040.050.0
Minor Allele Frequency (%)
Adapted from: Bogdanova et al. Hereditary Cancer in Clinical Practice 2013; 11:12
Figure 3: Rare mutations in a few highly penetrant genes are the largest contributors to breast cancer risk.
Syndromes such as Li-Fraumeni, Cowden, Peutz-Jeghers, and Hereditary Diffuse Gastric Cancer (HDGC) have been
known to significantly increase the risk for breast cancer [43-48]. Genetic testing of the genes associated with these
conditions (i.e., TP53, PTEN, STK11 and CDH1) has been part of the clinical management of patients with a family
history of breast cancer. Recently, PALB2 has been identified as an important contributor to breast cancer risk [4-6].
Table 3 summarizes the risk contributions from the top breast-cancer related genes.
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Gene
Syndrome
Neoplasm
BRCA1
HBOC
Breast (female), ovarian cancer
BRCA2
HBOC
Breast (male and female), prostate, pancreatic
TP53
Li-Fraumeni
PTEN
Cowden
STK11/LK81
Peutz-Jeghers
CDH1
HDGC
PALB2
PALB2-related
Breast cancer, sarcomas, leukemia, brain tumors, lung cancer,
adrenocortical carcinoma
Breast, thyroid, endometrial, kidney cancer
Breast, ovarian, cervical, uterine, testicular, small bowel,
colon cancer
Hereditary diffuse gastric, lobular breast
Breast, pancreatic, ovarian, male breast cancer
Table 3: high penetrance breast cancer genes and other associated cancer risks [3-6, 23, 24, 43-56].
Breast Cancer High Risk Genes
BRCA1
The BRCA1 (breast cancer 1, early onset) gene encodes a multifunctional protein that interacts with tumor
suppressors, DNA repair proteins, cell cycle regulators, RNA polymerase II holoenzyme, transcription factors,
corepressors, chromatin remodeling enzymes, and RNA processing factors. BRCA1, therefore, has a critical role in
maintaining genomic stability and is involved in many cellular processes important in tumor biology, including
DNA repair, cell cycle progression, and transcriptional regulation [1, 57-62]. Loss or inactivation of one copy of BRCA1 is
thought to result in accumulation of mutations and structural changes in the genome, thereby increasing risk
of cancer [63].
BRCA2
The BRCA2 (breast cancer 2, early onset) gene encodes a protein with important roles in the DNA damage response
and DNA repair pathways [1]. BRCA2 is a tumor suppressor that mediates recruitment of the RAD51 recombinase
protein to DNA double-strand breaks [1]. The primary function of the BRCA2 protein is to facilitate homologous
recombination, an important DNA repair mechanism in maintenance of genomic integrity [1, 63]. Loss or inactivation
of one copy of BRCA2 is thought to result in accumulation of mutations and structural changes in the genome,
thereby increasing risk of cancer [63].
CDH1
The CDH1 gene encodes the E-cadherin protein, a member of the trans-membrane glycoprotein family. E-cadherin
is expressed on epithelial tissues and is responsible for calcium-dependent cell-cell adhesion. Loss of CDH1
expression is associated with cancer cell invasiveness [64]. Cancers develop in individuals with a CDH1 germline
mutation when the second copy of the CDH1 gene is somatically inactivated or down regulated [64-67]. Germline
mutations in CDH1 have been shown to segregate in families with HDGC. It has been estimated that individuals
who are heterozygous for mutations in the CDH1 gene have a cumulative risk of diffuse gastric cancer of over
80% in both men and women by age 80 years, with a mean age at diagnosis of 40 years. In addition, female
heterozygotes have a cumulative risk of lobular breast cancer of 60% by age 80 years[50].
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PALB2
The PALB2 (partner and localizer of BRCA2) gene encodes a protein that plays essential roles in homologous
recombination (HR)-mediated DNA repair by interacting with breast cancer 1, early onset (BRCA1), breast cancer 2,
early onset (BRCA2) and other proteins involved in the HR DNA repair mechanism [68, 69]. Pathogenic PALB2 mutations
have been detected in 1-3% of BRCA1/2 mutation-negative hereditary breast cancer patients [68-71]. Although PALB2
mutations are relatively rare, some of the PALB2 mutations have been shown to confer a breast cancer risk that is
comparable to pathogenic mutations in BRCA1 and BRCA2 genes [72-74]. Clinical data suggest that PALB2 mutations
may also increase the risk for pancreatic cancer [75].
Fanconi anemia (FA) is a rare, recessive chromosome instability syndrome caused by mutations in at least one of
the several genes that encode FA pathway components [76]. FA is characterized by congenital abnormalities, bone
marrow failure, hypersensitivity to DNA crosslinking agents, defective DNA repair and cancer susceptibility [77, 78].
The PALB2 protein has been shown to be one of the component of FA pathway; certain biallelic mutations in PALB2
gene can cause a subtype of FA known as FA complementation group N (FANCN) [79, 80].
PTEN
The PTEN (phosphatase and tensin homolog) gene encodes a dual-specificity phosphatase that acts on both lipid
and protein substrates. The lipid phosphatase activity of PTEN suppresses the PI3K/AKT/mTOR signaling pathway,
which regulates cell growth and survival [81]. The importance of PTEN as a tumor suppressor gene is supported by
the high frequency of somatic mutations in PTEN found in a variety of sporadic human cancers [82].
PTEN harmatoma tumor syndrome (PHTS) is a collection of rare autosomal dominant disorders found in individuals
with deleterious germline mutations in the PTEN gene. Individuals with PHTS exhibit a spectrum of autosomal
dominant disorders involving disorganized growth of benign tumors called hamartomas in multiple organ systems
[83, 84]
. The two most common inherited PHTS disorders are the adult Cowden Syndrome (CS) and the pediatric
Bannayan-Riley-Ruvalcaba syndrome (BRRS) [84]. The PTEN-related Proteus syndrome (PS) and Proteus-like syndrome
are the two other types of PHTS.
STK11
The STK11 (also known as LKB1) gene encodes a serine-threonine kinase that is involved in the regulation of
metabolism, cell differentiation, proliferation, polarity and apoptosis [85, 86]. STK11 is a tumor suppressor, and
mutations in the gene have been associated with Peutz-Jehgers syndrome (PJS).
PJS has been associated with mutations in tumor suppressor gene STK11. PJS is an autosomal dominantly inherited
disorder that is characterized by hamartomatous polyps in the gastrointestinal tract, pigmented mucocutaneous
lesions and cancer predisposition. The hamartomatous polyps of PJS are most common in the small intestine but
can also occur in the stomach, large bowel and extraintestinal sites[48]. Gastrointestinal polyps can lead to chronic
bleeding resulting in anemia and increased risk of malignant transformation[48].
PJS is associated with increased risk for various malignancies, including colorectal, gastric, breast, gynecologic,
pancreatic and lung cancers, as well as tumors of the testes [48, 87, 88]. The risks among PJS patients for developing
any first cancer by ages 20, 30, 40, 50, 60 and 70 years are 2%, 5%, 17%, 31%, 60% and 85%, respectively [89]. In PJS,
malignancies appear at a younger age compared to the general population, i.e., an average age of 42 years [87].
Most patients who are clinically diagnosed with PJS have a causative mutation in STK11 [90]. Loss of kinase activity
is likely to be responsible for the development of this condition [91]. The clinical diagnosis of PJS is made when
a patient meets at least 2 of the following criteria: 2 or more Peutz-Jeghers polyps of the small intestine; typical
mucocutaneous hyper pigmentation; and a family history of PJS.
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TP53
The TP53 gene encodes a transcription factor that is involved in cellular responses to environmental and genotoxic
stress [92]. This tumor suppressor binds consensus DNA in the responsive elements of several hundreds of genes [93].
TP53 mutations are the most frequent genetic alterations in human cancers, with greater than 35,000 mutations
described in different types of cancer [94]. Approximately 95% of the mutations are localized in the DNA-binding
domain of TP53 [93].
Li-Fraumeni (LFS) and its variant, Li-Fraumeni-like (LFL) syndrome are autosomal dominant disorders caused by
germline mutations in TP53 (tumor protein p53) gene and are characterized by predisposition to multiple early
onset cancers [95]. LFS has high variability in penetrance, age of cancer onset and tumor spectrum [96]. LFL syndrome
is associated with incomplete LFS features [97]. The most common cancers associated with LFS are sarcoma, breast
carcinoma, brain tumors and adrenocortical carcinoma. Other cancers include leukemia, choroid plexus papilloma,
Wilms tumors, and gastric, colorectal and pancreatic cancer [98].
Clinically, LFS is diagnosed in individuals who have a germline mutation in TP53 gene, or if they meet the
established clinical criteria for LFS. At least 70% of clinically diagnosed LFS cases are associated with identifiable
germline mutations in TP53 gene.
Pathway Genomics Tests for Hereditary Breast and Ovarian Cancer
Given the diversity in patient’s medical and family histories, Pathway Genomics offers a wide range of testing
options to help determine the hereditary risk of breast and/or ovarian cancer. The testing options are summarized
in table 4.
Gene
Site
BRCATrue
Ashkenazi
Jewish
(3-site)
BRCA1
BRCA1
BRCA2
BRCA1
BRCA2
CDH1
PALB2
PTEN
STK11
TP53
185delAG
5382insC
6174delT
X
X
X
TM
BRCATrue
X
X
TM
BreastTrueTM
High Risk
Panel
X
X
X
X
X
X
X
BRCATrueTM
with reflex to
BreastTrueTM*
High Risk
Panel
X
X
X
X
X
X
X
BRCATrueTM
Ashkenazi
Jewish
(3-site) with
reflex to
BRCATrueTM*
X
X
X
X
X
Single Site
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
Table 4: Summary of Pathway Genomics genetic testing options for hereditary breast and or ovarian cancer. The asterisk (*) indicates that
reflex testing is triggered if a VUS or no reportable variant is found in the initial test.
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Potential Indications
The BRCATrue™ and BreastTrue™ line of tests is best suited for individuals with either a history of early onset breast
or ovarian cancer or a strong family history of breast and/or ovarian cancer. Analysis of personal and family medical
histories by medical professionals will help identify best tests to perform. The following are some of the medical
history details that may result in a recommendation for genetic testing:
•
•
•
•
•
•
•
Early onset breast cancer (especially if under 50 years of age)
Bilateral or multiple breast cancers
Diagnosed with both breast and ovarian cancer
Family history of breast and/or ovarian cancer
Two or more BRCA1 or BRCA2-related cancers in a single family member
Male breast cancer within family
Ashkenazi Jewish ethnic background
Test Technology
Pathway Genomics uses the most advanced Next Generation Sequencing (NGS) technology to search for mutations
in the coding regions of BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11 and TP53; regions of insufficient coverage by NGS
are sequenced using Sanger chemistry. Mutations found by NGS are confirmed using Sanger sequencing technology.
Sanger sequencing is also used for single-site detection including mutations in the BRCATrue Ashkenazi Jewish (3site) test. Large gene deletions and duplications are detected using array comparative genomic hybridization (aCGH).
Pathway’s sequencing tests display outstanding performance characteristics compatible with the highly demanding
genetic diagnostic applications (sensitivity: 99.99%, specificity: 99.997%, reproducibility: >99.99%).
Possible Outcomes
Pathway Genomics classifies variants using a 5-tier system based on the American College of Medical Genetics
(ACMG) guidelines. According to this system, variants are classified as either “Pathogenic”, “Likely Pathogenic”,
“Uncertain Pathogenicity (VUS)”, “Likely Benign” or “Benign”. Pathogenic, Likely Pathogenic and Uncertain Pathogenicity
(VUS) are always reported in the BRCATrueTM test. Likely Benign and Benign variants are not reported.
• Pathogenic: Mutations with known clinical significance and demonstrated to increase the risk of
cancer pathogenesis.
• Likely Pathogenic: Genetic changes that have some preliminary clinical data suggesting an
association with cancer but not sufficient to make a definitive determination of pathogenicity and
associated cancer risk.
• Uncertain Pathogenicity (VUS): Genetic changes with either no supporting data or the data are
conflicting, thus a determination of pathogenicity cannot be made.
• Likely Benign: Likely benign variants are genetic changes with strong but limited evidence to be classified
as benign and are not likely to increase the risk for cancer.
• Benign: Benign variants are genetic changes that are previously reported and have sufficient evidence to
be classified as benign with no clinical relevance.
Limitations and Warnings
The etiologies of cancer are multifactorial, that is cancer can occur as a result of various factors, including inherited
and acquired genetic mutations, diet, lifestyle choices and age. The BRCATrue and BreastTrue line of tests evaluates
only inherited genetic mutations. It is possible that mutations in genes and genetic regions not tested in Pathway
Genomics’ DNA sequencing test may contribute to an individual’s risk for cancer. Therefore, a negative test result,
where no mutations are detected does not eliminate the individual’s cancer risk.
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