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Endometrial Cancer
Hereditary Endometrial Cancer
A Guide for Clinicians
KNOWING WHAT TO LOOK FOR KNOWING WHERE TO LOOK AND KNOWING WHAT IT MEANS
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Hereditary Endometrial Cancer Panel
Advances in molecular genetics have led to the identification of numerous
genes associated with inherited susceptibility to endometrial cancer. While
the majority of endometrial cancer is not inherited, approximately 2-3%
of endometrial cancers are associated with Lynch syndrome (LS)1 and
approximately 5% of individuals with papillary serous endometrial cancer
have a mutation in a non-LS associated gene.2 Clinical diagnostic and/
or testing criteria have been established for several hereditary cancer
syndromes associated with an increased risk of endometrial cancer.
However, the personal and family histories of many patients suspected
of having a hereditary predisposition do not always fulfill these criteria. In
addition, the patient’s personal or family history may raise suspicion for
several hereditary conditions. A step-wise approach to genetic testing
in these patients can be complicated, costly and time consuming. The
Endometrial Cancer Panel offered at GeneDx is a comprehensive panel
that utilizes next generation sequencing and exon-level microarray to
identify mutations in 11 genes associated with a hereditary predisposition to
endometrial cancer.
Genes Included in the Endometrial Cancer Panel
The 11 genes included in the Endometrial Cancer Panel can be categorized
into two main groups: High-Risk Genes and Moderate/Newer Risk Genes as
described in Table 1.
High-Risk Genes
Moderate/Newer Risk Genes
• Genes Included: MLH1, MSH2, MSH6,
PMS2, EPCAM, PTEN
• Genes Included: BRCA1, BRCA2, TP53,
MUTYH, CHEK2
• Well studied
• Not as well studied with regard to endometrial
cancer risk
• Significantly increased risk of developing
endometrial cancer (often at least 4-fold)
• Data may be based on a small number of
patients or a specific ethnic group
• Increase risk for other cancers
• Precise lifetime risks of endometrial cancer
may not be determined
• Guidelines for screening and prevention
established
• Increase risk for other cancers
• Guidelines for screening and prevention
related to endometrial cancer risk not yet
established
Table 1: Composition of the Endometrial Cancer Panel
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The High-Risk Genes category includes genes associated with welldefined cancer syndromes that cause significantly increased risk for
endometrial cancer. The Moderate/Newer Risk Genes category includes
genes that impart a moderate risk for endometrial cancer or have been
identified in families with reported endometrial cancer, but precise
lifetime risks for endometrial cancer have not been determined and/or
need to be confirmed.
Lifetime Cancer Risks
High-Risk Genes
The Endometrial Cancer Panel includes highly penetrant genes associated
with well-defined cancer syndromes with increased risk for endometrial
cancer as well as other cancers. These include:
Lynch syndrome (LS) - MLH1, MSH2, MSH6, PMS2, EPCAM
Lynch syndrome is characterized by increased risks for cancers of the
colon/rectum, endometrium, stomach, small bowel, ovaries, pancreas,
biliary tract, and urothelium. Some individuals with Lynch syndrome develop
sebaceous adenomas/carcinomas and keratoacanthomas of the skin
(sometimes referred to as Muir Torre variant) or develop brain tumors, such
as glioblastomas (sometimes referred to as Turcot variant). Colorectal cancer
and endometrial cancer are the two most common cancers observed in
individuals with Lynch syndrome. Several studies have been conducted
to determine the lifetime risk of colorectal, endometrial and the other
Lynch syndrome-associated cancers, and have resulted in a wide range of
estimates. Table 2 provides estimates for cancers associated with mutations
in each of these genes. The average age of endometrial cancer diagnosis is
between 45-59 years.3,4 Individuals with LS who have been diagnosed with
colon or endometrial cancers have an increased risk for a second primary
diagnosis of a Lynch syndrome-associated cancer.5,6
PTEN hamartoma tumor syndrome (PHTS) - PTEN
Mutations in the PTEN gene are responsible for the PTEN hamartoma tumor
syndrome (PHTS), a term used to describe the different conditions caused
2
High-Risk Genes
Moderate/Newer Risk Genes
Genes
Associated Cancers and Risks
EPCAM*
Endometrial (12-55%), Colorectal (69-75%), Ovarian, Gastric, Pancreatic,
Biliary tract, Urothelium, Small bowel, Brain, Sebaceous neoplasms7
MLH1
Endometrial (31-54%), Colorectal (22-80%), Ovarian (13-20%), Gastric (6-20%),
Pancreatic, Biliary tract, Urothelium, Small bowel, Brain, Sebaceous neoplasms8,9,10,11,12
MSH2
Endometrial (31-61%), Colorectal (22-80%), Ovarian (10-24%), Gastric (<1-9%),
Pancreatic, Biliary tract, Urothelium, Small bowel, Brain, Sebaceous neoplasms8,9,10,11,12
MSH6*
Endometrial (44%), Colorectal (20-44%), Ovarian (1-11%), Gastric, Pancreatic, Biliary tract,
Urothelium, Small bowel, Brain, Sebaceous neoplasms13,14
PMS2*
Endometrial (15%), Colorectal (15-20%), Ovarian, Gastric, Pancreatic, Biliary tract,
Urothelium, Small bowel, Brain, Sebaceous neoplasms14
PTEN
Endometrial (5-10%), Female breast (25-50%), Thyroid (10%), Colon, Renal,
Melanoma15,16,17
BRCA1
Female breast (57-87%), Ovarian (24-54%), Prostate, Male breast, Pancreatic,
Fallopian tube, Primary peritoneal, Endometrial (papillary serous)18,19,20,21,22,23,24,25,26,27,28,29
BRCA2
Female breast (41-84%), Ovarian (11-27%), Prostate (20-34%), Pancreatic (5-7%),
Male breast (4-7%), Fallopian tube, Primary peritoneal, Endometrial (papillary serous),
Melanoma18,21,22,27,28,29,30,31,32,33
MUTYH
Colorectal (80%), Duodenal (4%), Endometrial34,35,36
TP53
Female breast, Soft tissue sarcoma, Osteosarcoma, Brain, Hematologic malignancies,
Adrenocortical carcinoma. Overall risk for cancer: 100% in females, 73% in males37,38,39
CHEK2
Female breast, Male breast, Colon, Prostate, Thyroid, Endometrial (papillary serous),
Ovarian2,40,41,42,
Table 2: Cancers and Lifetime Risks Associated with Genes in the Endometrial Cancer Panel
*Tumor spectrum is representative of Lynch syndrome; data are limited with regard to the association of certain
cancers with mutations in MSH6, PMS2, and EPCAM.
by PTEN mutations, including Cowden syndrome (CS), Bannayan-RileyRuvalcaba syndrome (BRRS), and Proteus/Proteus-like syndrome. Both
CS and BRRS are characterized by increased risk for malignant tumors
of the breast, endometrium, thyroid, colon, kidneys and skin. The risk of
endometrial cancer is estimated to be 5-10% in individuals with CS or BRRS.
Risk estimates for other cancers are outlined in Table 2. In addition to cancer
risks, individuals with CS typically have one or more distinctive features,
including an increased head circumference ≥97th percentile (macrocephaly),
trichilemmomas, papillomatous papules, and the pathognomonic finding
of cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease). CS is
also associated with benign conditions, including benign breast disease,
CLINICIAN GUIDE FOR HEREDITARY ENDOMETRIAL CANCER
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thyroid goiters, benign gastrointestinal polyps, and uterine fibroids. BRRS is
associated with macrocephaly, intestinal hamartomas, pigmented macules of
the glans penis, and can be associated with developmental delay or autism.
Moderate-Risk and Newer-Risk Genes
In addition to the high-risk genes, this panel includes 5 moderate/newer risk
genes: BRCA1, BRCA2, MUTYH, TP53 and CHEK2. While these genes
may be well-described and/or associated with high risk for other cancers,
their role in endometrial cancer risk is either moderate or newly described.
Consensus guidelines for endometrial cancer screening and prevention are
not currently available for these genes. Recommendations are generally
based on cancer family history and expert opinion. Table 2 provides lifetime
cancer risks (when available).
Inheritance of the Genes in the Endometrial
Cancer Panel
The majority of genes in the Endometrial Cancer Panel are inherited
in an autosomal dominant manner. Therefore, an individual carrying a
disease-causing mutation in any of the genes above has a 50% chance of
transmitting the mutation to a child, either male or female. Most individuals
with a mutation in one of the genes on the panel inherited it from a parent,
and therefore the siblings of an individual with a mutation have a 50%
chance of carrying the same disease-causing mutation. The risk for other
family members to inherit the same mutation depends on which side of the
family transmits the mutation and how closely related the family member is to
your patient.
Mutations in the MUTYH gene are inherited in an autosomal recessive
manner; hence, two mutations (one in each copy of the gene from each
parent) are generally required to produce symptoms. Of note, some studies
have shown that people who carry just one MUTYH mutation may have an
increased risk for certain cancers, including colon cancer, endometrial cancer
and breast cancer, but these risks are not well defined. Parents and children
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of an individual with two MUTYH mutations are obligate carriers (e.g., 100%
risk to have at least one mutation), and their full siblings have a 25% chance
of having two mutations and a 50% chance of having one mutation in the
MUTYH gene. First-degree relatives of individuals who carry one MUTYH
mutation have a 50% chance of also testing positive for the mutation.
While each of the dominantly inherited genes on the panel is associated
with an increased risk for endometrial cancer when a single mutation in
the gene is present, some of the genes on the panel are also associated
with rare autosomal recessive syndromes if an individual has a mutation
in both copies of the gene (biallelic mutations). The genes known to be
associated with recessively inherited syndromes are listed in Table 3. If both
a mother and father are carriers for a mutation within the same gene*, each
of their children has a 25% chance to inherit both mutations, resulting in the
recessive syndrome associated with that particular gene. If your patient tests
positive for one of these mutations and wishes to have children in the future,
then careful review of his or her partner’s family history and possible genetic
testing of the partner would be needed to assess the reproductive risks
associated with mutations in these genes.
Genes
MLH1, MSH2, MSH6, PMS2, EPCAM
Autosomal Recessive Disorders
Constitutional mismatch repair deficiency syndrome
*there is a case report of a child with this condition that
has one mutation in EPCAM and one mutation in MSH2.
BRCA2
Fanconi anemia
MUTYH
MUTYH-associated polyposis (MAP)
Table 3: Genes Associated with Autosomal Recessive Disorders
Genetic Counseling
Pre-test counseling is recommended for individuals who are either interested
in understanding their risks and/or meet the clinical criteria for testing and are
considering genetic testing. If a disease-causing mutation has already been
identified in a family member, testing of the specific mutation is appropriate.
If a disease-causing mutation has never been identified, an affected family
member with the highest likelihood for a positive result (early onset disease,
CLINICIAN GUIDE FOR HEREDITARY ENDOMETRIAL CANCER
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bilateral disease or multiple primaries) is ideally the best person for initial
testing within a family. If an affected family member is not available for
testing, testing of an unaffected family member can be performed, although
a negative test result will not guarantee that the individual does not have an
increased cancer risk. Once patients make the decision to undergo testing,
post-test genetic counseling is recommended to understand the implications
of the results. Genetic counseling services across the country can be found
at: www.nsgc.org
Clinical Indications for the Endometrial Cancer Panel
The Endometrial Cancer Panel is appropriate for individuals
whose personal and/or family history is suggestive of a hereditary
predisposition to endometrial cancer. This includes:
• Individuals diagnosed with endometrial cancer at an age ≤50
• Individuals with a family history of endometrial cancer
in multiple close relatives or a relative with early-onset
endometrial cancer (≤50)
• Individuals with multiple primary cancers including endometrial
cancer
• Individuals with several relatives affected with relevant cancers
spanning multiple generations
The Endometrial Cancer Panel is also appropriate for individuals
whose personal and/or family history is suggestive of both
Hereditary Breast and Ovarian Cancer syndrome (BRCA1/BRCA2)
and Lynch syndrome, even in the absence of endometrial cancer.
This panel includes a number of high-risk breast and ovarian cancer
genes, as well as genes predisposing to colon cancer without
polyposis. Indications include:
• Individuals with a personal and/or family history of breast cancer
and colon cancer
• Individuals with a personal and/or family history of ovarian
cancer and colon cancer
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Genetic Test Results and What They Mean
There are three possible outcomes of genetic testing: positive, negative
and variant of unknown significance (VUS). All patients who undergo
genetic testing should receive pre-test and post-test genetic counseling to
understand the implications of testing. Genetic counseling services across
the country can be found at: www.nsgc.org
Positive Result
A positive result indicates that a disease-causing mutation was identified
in that individual and the risk for cancer is increased. Knowledge of a
positive result provides valuable information to the patient, physician and
family members. Knowledge of a patient’s genotype can assist in making
management and treatment decisions. Furthermore, testing of the patient’s
family members can allow for accurate cancer risk predictions.
Negative Result
A negative result means that a disease-causing mutation was not identified
in the individual tested. A negative result can have different interpretations
based on the following scenarios:
True Negative Result: An individual who tests negative for a known familial
mutation is not a carrier of a known cancer-predisposing gene that has
been positively identified in another family member. The risk for cancer
in this individual is generally not expected to be greater than that for the
general population. In some cases, this interpretation may be limited by the
identification of a mutation in a gene with modest cancer risk or a mutation
in a gene that has been recently described (i.e., newer genes previously
described) with cancer risk and for which there are currently limited data
to predict this risk. In these situations, not all of the cancer in the family
may be attributed to the identified familial gene mutation. Therefore, clinical
assessment of the complete family history of cancer and personal risk
factors is important to determine appropriate management.
Uninformative Negative Result: If testing was performed on an individual with
a cancer diagnosis, this means that we do not have an explanation for why
this individual developed cancer. Genetic counseling is recommended, as
additional testing may be considered based on the individual’s medical and
family history. If testing was performed on an individual without a personal
CLINICIAN GUIDE FOR HEREDITARY ENDOMETRIAL CANCER
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history of cancer and based only on family history, the risk for cancer may
remain increased, as the exact cause of the cancer in the family remains
unknown. Testing of an affected family member may help clarify this
individual’s cancer risks.
Variant of Unknown Significance (VUS)
A variant of unknown significance (VUS) indicates that the pathogenicity
of the variant cannot be clearly established. To further clarify the clinical
significance of this variant, testing of family members may be helpful. If
a relative with a related cancer is found to have the same variant, it may
provide evidence that the variant is disease-causing. The greater the number
of affected family members who carry the VUS, the greater is the likelihood
that the VUS is pathogenic. With consistent linkage of the VUS to family
members with related cancers, in addition to other evidence, the variant
found may be reclassified as a family-specific mutation and predictive
genetic testing can be offered to extended family members. Conversely, a
VUS could be determined to be benign through this and other research.
GeneDx will review a patient’s detailed family history to determine if family
members are eligible for complementary targeted variant testing through our
Variant Testing Program.
Management
There are a variety of management strategies available to patients who
test positive for a disease-causing mutation in a gene associated with an
increased risk of endometrial cancer. Various guidelines outline available
options and recommendations for patients who test positive for a number
of syndromes associated with hereditary endometrial cancer. These options
include increased screening and surgery. The guidelines below are examples
of current recommendations as of 2014. Please visit: www.nccn.org for the
most up-to-date recommendations, including ages to begin surveillance and
current screening frequencies.
Lynch Syndrome Related Cancers
Increased screening:
• Frequent colonoscopy (every 1-2 years in many cases) starting at an
early age
8
• Consider endometrial cancer screening, which may include
endometrial biopsy, transvaginal ultrasound and CA-125 blood tests
• Consider routine esophagogastroduodenoscopy (EGD) with extended
duodenoscopy starting at an early age
• Consider routine urinalysis starting at an early age
• Annual physical exam
Risk reducing surgery:
• Consider the option of colectomy, particularly if the patient requires
surgery to address a colonic neoplasm not amenable to endoscopic
resection. This surgery will reduce the chance of developing colon
cancer by more than 90%.
• Hysterectomy and salpingo-oopherectomy can be considered once a
woman has completed childbearing. This surgery greatly reduces the
chance of developing endometrial or ovarian cancer.
PTEN Related Cancers
For women, increased screening includes the following:
• Breast awareness, including routine self breast exam
• Routine clinical breast exam starting at an early age
• Breast MRI and mammography starting at an early age
• Regarding endometrial cancer screening, consider endometrial biopsy
and/or transvaginal ultrasound beginning at an early age; encourage
patient education and prompt response to symptoms
For men and women, increased screening includes the following:
• Annual physical exam
• Baseline thyroid ultrasound at an early age and consider routinely
thereafter
• Routine colonoscopy starting at an early age
• Consider routine renal ultrasounds starting at an early age
• Consider routine dermatologic exam
Risk reducing surgery:
• Options of mastectomy and hysterectomy can be discussed
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Other Genes
Management guidelines for additional genes are outlined in Table 4. For
comprehensive gene-specific guidelines, please visit: www.nccn.com
Genes
Management Guidelines
TP53
• Consider increased colonoscopy screening
• Comprehensive physical exam including skin and neurologic exams
• Use caution regarding radiation therapy for cancer
• Increased breast awareness, including self breast exam
• Clinical breast exam
• Breast MRI and mammography starting at an early age
• Consider prophylactic mastectomy
BRCA1/
BRCA2
• Increased breast awareness, including self breast exam
• Routine clinical breast exam
• Breast MRI and mammography starting at an early age
• Consider transvaginal ultrasound of ovaries and CA-125 blood tests
• Consider full body skin exam
• Consider pancreatic cancer screening
• Routine prostate cancer screening starting at an early age
• Consider the use of risk-reducing medications (such as tamoxifen,
raloxifene and oral contraceptives)
• Consider prophylactic mastectomy
• Salpingo-oopherectomy is recommended (as early as the 30s-40s) once a
woman has completed childbearing
MUTYH
(Biallelic
Mutations)
• Annual physical exam
• Frequent colonoscopy starting at an early age
• Consider routine esophagogastroduodenoscopy (EGD) and side viewing
duodenoscopy starting at an early age
CHEK2
• Consider breast MRI in addition to mammography
Table 4: Management Guidelines for Additional Genes
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Resources for Patients:
• American Cancer Society www.cancer.org
• National Cancer Institute www.cancer.gov
• National Society of Genetic Counselors www.nsgc.org
•GeneDx www.genedx.com
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How can I order this test?
You can order this test by taking the following steps:
1. Download the OncogeneDx test requisition form from the GeneDx
website: www.genedx.com/forms
2. Complete all the forms with required information
3. Ship completed forms along with two 4mL lavender top tubes of blood
samples per person to the following address:
Accessions
GeneDx
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Gaithersburg, MD 20877
We provide shipping kits to physicians upon request. To place an order for
shipping kits, please visit our website: www.genedx.com/supplies or email
us at: [email protected]
About GeneDx
GeneDx is a highly respected genetic testing company, founded in 2000
by two scientists from the National Institutes of Health (NIH) to address the
needs of patients and clinicians concerned with rare inherited disorders.
Currently, GeneDx offers whole exome sequencing, oligonucleotide
microarray-based testing for detecting chromosomal abnormalities, testing
for inherited eye disorders and autism spectrum disorders and gene panels
for testing various forms of inherited cardiac disorders, mitochondrial
disorders, neurological disorders and inherited cancer disorders. At GeneDx,
our technical services are matched by our scientific expertise and customer
support. Our growing staff includes more than 40 geneticists and genetic
counselors specialized in clinical genetics, molecular genetics, metabolic
genetics and cytogenetics who are just a phone call or email away. We invite
you to visit our website www.genedx.com to learn more about us and the
services we offer.
207 Perry Parkway
Gaithersburg, MD 20877
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© 2014 GeneDx. All rights reserved. 91455 11/14
Information provided in this guide is current as of 011/2014.