Kylie, Olivia, Cody, Isabella and Averi - June, 2010. We now know Cody, Averi and Isabella all suffer from Lynch Syndrome III

Saturday, January 31, 2015

If your child has cancer and Cafe-au-Lait spots, a new type of Lynch Syndrome may be the cause!

A New Type of Lynch Syndrome: Childhood Cancers and Café-au-Lait Spots

Sara Pirzadeh, M.S., C.G.C.
Certified Genetic Counselor
Moncrief Cancer Resources/UT Southwestern Medical Center

Several of these articles have discussed Lynch syndrome (LS) and its general features, including increased colon and uterine cancer risk, amongst others. As you know, LS is a dominantly- inherited cancer syndrome, with only 1 copy of a mismatch repair gene mutation (MLH1,MSH2,MSH6,PMS2) needed to cause increased lifetime cancer risk (otherwise known as monoallelic mutation). In this month’s article, we will focus on a recessively-inherited form of LS, where an individual has 2 copies of a LS-related gene with a mutation (otherwise known as biallelic mutations).

Monoallelic mutations in MLH1 and PMS2 were reported in individuals with colorectal cancer and brain tumors at excessively young ages in 1995, with additional biochemical evidence that led researchers to believe an additional gene mutation was contributing to the phenotype2. It was only in 2004 when the biallelic mutation was discovered in the affected individuals3,4. These patients are characterized by development of childhood cancers, including hematological malignancies and/or brain tumors, which are not typical for LS. Some also have earlier-onset colorectal cancers when compared to monoallelic LS mutation carriers, and almost all show characteristics similar to those of neurofibromatosis I (NF1, mainly café-au-lait spots)1. It has been suggested that any child presenting with multiple café-au-lait spots and early-onset malignancy that is not clearly NF1 associated should be tested for mismatch repair gene mutations.

Unlike other DNA repair deficiency syndromes (i.e. Fanconi Anemia, etc.), growth parameters are usually within the normal range. Affected children typically have not required medical attention prior to onset of malignancy. This diagnosis can be missed, delayed, or mistaken for other conditions, particularly NF1. It can also be missed when the monoallelic mutation carriers may not manifest the pathognomonic LS cancers until after an affected biallelic carrier has2.

A review by Wimmer and Etzler in 2008 examined the genetic, clinical and pathological findings per gene as documented in 78 patients from 46 families. The largest group (43 patients) carried biallelic PMS2 mutations, while 14 patients carried biallelic MLH1 mutations and 8 carried biallelic MSH2 and MSH6 mutations. Tumors documented could be classified into 4 groups: hematologic, brain, LS, and other (neuroblastoma, Wilms tumor, ovarian neuroectodermal tumor, sarcoma, etc.). The most prevalent brain tumors are astrocytomas (primarily glioblastomas), and 4 patients developed medulloblastoma. Interestingly, 5 patients developed supratentorial primitive neuroectodermal tumors (SPNET), all of whom were PMS2 biallelics. The most common hematological malignancies are non-Hodgkin lymphoma and acute lymphoblastoid leukemia, and acute myeloid leukemia was noted in 3 patients (one as a first malignancy).

Overall, hematological malignancies seem to arise in infancy or early childhood (~5.5 years), while brain tumors tend to arise in later childhood (~8 years). LS tumors, primarily colorectal cancer, usually arise in adolescents (~16 years). Colorectal cancer can be the second or third malignancy in patients that survived their first tumor. MLH1 and MSH2 biallelic mutation carriers tend to have an earlier age of malignancy onset (mean 3.5 years) in comparison with MSH6 or PMS2 biallelic mutation carriers (mean 9 years).

 Hematologic tumor prevalence has been higher in patients with MLH1 or MSH2 biallelics, and the incidence of brain and LS-associated tumors has been higher in MSH6 or PMS2 biallelics. The likelihood of surviving the first tumor and to develop a different second (or third) cancer is higher in MSH6 or PMS2 biallelics. This trend follows monoallelic LS carriers, where those with MLH1/MSH2 mutations tend to have a more severe and earlier presentation than MSH6/PMS2 carriers. 

As discussed in previous articles, microsatellite instability (MSI) in tumor tissue is a hallmark criterion of LS. In biallelic patients, various tumor tissues were analyzed for MSI. In all LS-related tumors in biallelic patients analyzed so far, MSI has been reported. MSI was also tested in eight of the brain tumors (7 glioblastomas and 1 oligodendroglioma), and only 3 displayed MSI. Immunohistochemical (IHC) testing on tumor tissues is another diagnostic exam for LS discussed in previous articles. IHC testing was also performed on tumor tissue from biallelics, all of which showed lack of protein expression (therefore, an abnormal test result, indicative of mismatch repair gene dysfunction). This leads us to believe that IHC would be the preferable test on tumor tissue in those where biallelic mutations are suspected1.

There is evidence from in vitro data that monoallelic mismatch repair gene mutations may confer resistance to certain chemotherapeutics and may increase their mutagenic potential5. Practically speaking, certain chemotherapy agents are not useful in treating LS-related tumors and can even cause increased risk of secondary cancers. This article suggests that avoidance of certain chemotherapeutics, such as O6-methylating agents, may be considered when defining treatment options for patients with biallelic mutations.

To date, there is not a consensus statement regarding surveillance for known biallelic mutation carriers. These children have increased risk for a wide spectrum of malignancies, which makes delineating a surveillance program difficult. Research is ongoing in this respect to provide a pragmatic approach for screening affected individuals. This information is also useful for the relatives of affected individuals, as siblings would have a 25% risk for this condition. Given the known childhood onset of malignancies in this case, prenatal diagnosis and preimplantation genetic diagnosis (PGD) would be appropriate options to discuss with these families if they are interested.

The similar presentation in biallelics (and distinct difference in presentation from LS) has prompted some to call this ‘mismatch repair-deficiency syndrome’, ‘constitutional mismatch repair- deficiency syndrome’, or ‘Lynch syndrome 3’. Whatever its name, this newly defined syndrome is important to be aware of when evaluating patients with LS or children with café-au-lait spots and malignancies. As always, if you have any questions regarding this or evaluation of your patients, please contact my office at 817-838-4871.

1. Wimmer and Etzler. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 2008; 124:105-22.
2. Rahman and Scott. Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Human Molecular Genetics 2007; 16:Review Issue 1, R60-66.
3. Menko, et al. A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 2004; 3:123-27.
4. De Vos, et al. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 2004; 74:954-64.
5. Scott, et al. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol 2007b; 4:130-34. 

Turcot Syndrome

Turcot Syndrome

This section has been reviewed and approved by the Cancer.Net Editorial Board11/2013

What is Turcot syndrome?

Turcot syndrome is a condition in which cells become abnormal and form masses called polyps. A polyp is benign (noncancerous) but can eventually turn malignant (cancerous, meaning it can spread to other parts of the body). Turcot syndrome is rare and is considered to be an alternative form of two more common syndromes associated with polyp formations: Lynch syndrome and familial adenomatous polyposis (FAP).

People with Turcot syndrome have multiple adenomatous colon polyps (polyps in the colon made up of cells that form mucus), an increased risk of colorectal cancer, and an increased risk of brain cancer. The type of brain cancer generally depends on whether the Turcot syndrome is more similar to Lynch syndrome or FAP. The two most common types of brain tumors in Turcot syndrome are:

  • Glioblastoma. This type of brain tumor is a very aggressive form of astrocytoma that is commonly found in families who have features of Lynch syndrome.
  • Medulloblastoma. This type of brain tumor begins in granular cells in the cerebellum (back of the brain). Medulloblastoma most often occurs in children and is commonly found in families who have features of FAP.

What causes Turcot syndrome?

Turcot syndrome is a genetic condition. This means that the risk of Turcot syndrome can be passed from generation to generation in a family. In families with glioblastoma and other features of Lynch syndrome, mutations (alterations) have been found in two genes: MLH1 and PMS2. In families with medulloblastoma and other features of FAP, mutations have been found in the APCgene. 

How is Turcot syndrome inherited?

Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. Turcot syndrome follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting that disease. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. 

How common is Turcot syndrome?

Turcot syndrome is considered to be rare.

How is Turcot syndrome diagnosed?

A person with multiple adenomatous colon polyps and/or colorectal cancer, along with either glioblastoma or medulloblastoma, may have Turcot syndrome. Blood tests are available to look for the three genes linked to Turcot syndrome. People who may have Turcot syndrome can have a blood test to look for a mutation in the APC gene associated with FAP or the MLH1 gene associated with Lynch syndrome. They may also have testing for the mutation in PMS2 if Turcot syndrome is suspected. If a specific gene mutation is found, other family members may also be diagnosed with Turcot syndrome if they are tested and have the same gene mutation. However, some families that appear to have Turcot syndrome may not have a detectable gene mutation.

What are the estimated cancer risks associated with Turcot syndrome?

The risks of cancer and other features depend on whether the Turcot syndrome appears to be more similar to Lynch syndrome or FAP; visit the sections for those conditions for a summary of cancer risks and other features.

What are the screening options for Turcot syndrome?

The screening options for Turcot syndrome are considered to be similar to those for Lynch syndrome or FAP, with the addition of screening for brain cancer. See those conditions’ sections for a summary of screening recommendations.

There are no specific guidelines for the frequency and method of screening for brain cancer. Individuals from families diagnosed with Turcot syndrome are encouraged to talk with a neurologist (a doctor who specializes in problems with the brain and central nervous system) about screening options.

Screening options may change over time as new technologies are developed and more is learned about Turcot syndrome. It is important to talk with your doctor about appropriate screening tests.

Learn more about what to expect when having common tests, procedures, and scans.

Questions to ask the doctor

If you are concerned about your risk of colorectal cancer or brain cancer, talk with your doctor. Consider asking the following questions of your doctor:

  • How many colon polyps have I had in total?
  • What type of colon polyps have I had? (the two most common kinds are hyperplastic and adenomatous)
  • What is my risk of developing colorectal cancer?
  • What is my risk of developing brain cancer?
  • What can I do to reduce my risk of cancer?
  • What are my options for cancer screening?

If you are concerned about your family history and think your family may have Turcot syndrome, consider asking the following questions:

Additional resources

Guide to Lynch syndrome

Guide to Familial Adenomatous Polyposis(FAP)

Guide to Colorectal Cancer

The Genetics of Colorectal Cancer

Guide to Brain Tumor

What to Expect When You Meet With a Genetic Counselor

Colon Cancer Alliance

Colorectal Cancer Coalition (C3)

Lynch Syndrome International

National Cancer Institute

American Cancer Society


To find a genetic counselor in your area, ask your doctor or visit the following websites:

National Society of Genetic Counselors

National Cancer Institute: Cancer Genetics Services Directory

Friday, January 30, 2015

Cody's 22nd birthday and a sign from God!

We lost our Doberman, Chloe, to cancer in May of last year. I was heartbroken! She spent many nights at hospice with Averi and I.
The last couple of months I have been searching online in hopes of finding a new dog. Today someone emailed 2 puppies they have available for adoption. One of the puppies name is Cody....and today would have been his 22nd birthday! I don't believe in coincidences. Thank you God for giving me a sign from heaven that Cody is ok!

Wednesday, January 28, 2015

Man beats stage 3 colon cancer naturally!

Chris Wark
Wark Family Photo 2012 scan 2
I’m currently wearing about 8 hats…
I’m a husband, father, real estate investor, 
musicianchemo-free cancer survivor, blogger,
health coach, and public speaker.
How do I do it all? I have no idea!
The cliff notes version of my story:
In December 2003 I was diagnosed with Stage 3 Colon Cancer. There was a golf ball sized tumor in my large intestine and the cancer had spread to my lymph nodes. It was two weeks before Christmas and I was 26 years old.
The oncologist told me I was “insane” but I decided against chemotherapy after surgery.
After prayerful consideration I radically changed my diet and did every natural non-toxic therapy I could find.
I started this blog in 2010 to share my story and everything I’ve learned about nutrition and natural therapies for cancer. I didn’t expect it to blow up, but it has.
Fast forward to 2013
Ten years later, by the grace of God, I’m still alive and kicking and in the best health of my life.
My wife and I have two beautiful daughters, Marin (8) and Mackenzie (5).
I thank Him every day for my life, health and healing.
You are probably here for one of three reasons:  
1) You have cancer, and you don’t like the options you’ve been given.
2) Someone you care about has cancer and you want to help them.
3) You want to transform your health and reduce your risk of ever developing cancer.
Whatever your reason, you’ve come to the right place! The information I’m sharing here saved my life. And the good news is these principles are holistic, they don’t just apply to cancer…
The human body is Intelligently Designed to heal itself, and given the proper nutrients and care, it will.
Despite what conventional doctors may have told you…

Your body can heal.

I’m not going to give you pseudo-healthy tips like:  “Follow the food pyramid, eat a low-fat diet, count your calories, drink diet soda instead, use artificial sweeteners,” etc. That kind of lousy advice is the reason so many of us are sick now!
What you’re going to get from me is Hardcore Health Advice:
The absolute healthiest way I know to live, which is how I beat cancer.

Despite what doctors may have told you, you have options.
You have the power to transform your health.
If I did it, you can too!

New Immunotherapy Vaccine shows promise in treating Brain Tumors

New Immunotherapy Vaccines Show Promise in Treating Brain Tumors

Researchers in Dana-Farber’s Center for Neuro-Oncology are now launching attacks on glioblastomas from a new angle – by turning the patient’s immune system against the cancer cells. Where targeted chemotherapy uses drugs to disable proteins that cancer cells need to grow, immunotherapy drugs stimulate the patient’s immune system to recognize and kill cancer cells.
David Reardon, MD, brain tumors
David Reardon, MD
Traditional drugs and even targeted chemotherapy agents have had little success in treating glioblastoma – the deadliest type of brain tumor.
“Immunotherapy represents a great hope for patients currently facing this disease,” says David Reardon, MD, clinical director of the Center.  “We’re anxious to move this approach forward for brain cancer patients.”
Last November, Reardon reported that a new cancer vaccine, rindopepimut, showed promise in a clinical trial of patients whose glioblastoma cells contain a particular gene mutation.
Cancer vaccines are a form of immunotherapy that have been studied and tested for many years with some success. They’re often made from an individual patient’s tumor cells, or parts of them, which are processed in the laboratory and returned to the patient to stimulate a strong immune response.
Rindopepimut, given along with the anti-angiogenic drug Avastin, significantly improved the survival of patients whose tumors carried the mutation known as EGFRvIII, which is found in about one-third of glioblastoma tumors.
“This is the first randomized clinical trial of immunotherapy to show a survival benefit in glioblastoma,” Reardon says. “It is a very nice proof of concept.”
Reardon is also heading a new clinical study of NeoVax, a “personalized neoantigen cancer vaccine,” which is already in testing for melanoma at Dana-Farber.
The NeoVax vaccine is made with “tumor-specific antigens” that correspond to the unique set of such antigens on the surface of an individual patient’s tumor cells. It’s been shown that these highly specific antigens can stimulate a potent, focused immune response.
“We think NeoVax should be effective even if the tumor tries to change to become treatment-resistant,” Reardon says.
The new pilot study, done in collaboration with Dana-Farber scientists Catherine Wu, MD, and Edward Fritsch, PhD, is testing the feasibility and safety of NeoVax in 15 patients.
If the vaccine proves effective, it will be combined in further trials with immune checkpoint blockers that target proteins PD-1 and PD-L1 to remove the brakes that cancer uses to suppress an immune response. New drugs that attack these checkpoints have had dramatic and long-lasting results in some patients with advanced, metastatic melanoma.
In a parallel project currently being tested in animal models, Reardon, in collaboration with David Mooney, PhD of the Wyss Institute, is optimizing an implantable “matrix” of biomaterials designed to reprogram immune cells in the patient’s body to generate a potent immune attack on glioblastoma tumors.

Monday, January 26, 2015

Parents of Kids with Cancer Suffer Post-Traumatic Stress Syndrome

Parents of Kids with Cancer Suffer Post-traumatic Stress

Article date: January 13, 2006

Symptoms Most Common During Treatment

Summary: A study of the parents of children undergoing treatment for cancer finds that in most of the families, at least one of the parents has symptoms of post-traumatic stress. Although the symptoms may fade with time, they can interfere with the care of the child and the parent's well-being, researchers from the Children's Hospital of Philadelphia report in the Journal of Clinical Oncology.
Why it's important: In the past, parents who were having trouble dealing with their child's illness were thought to be either "anxious" or "depressed." But the parents may really be having symptoms of post-traumatic stress, which can be far more damaging. Parents who experience these symptoms may have trouble complying with their child's caregiving needs. They may respond inappropriately to health care providers. The family may not function well when cancer treatment is over. Recognizing the post-traumatic symptoms and helping parents overcome them may avoid these problems.
What's already known: Post-traumatic stress has been recognized for thousands of years. Many people who have had a traumatic experience such as a personal assault, or have been in combat, or experienced a catastrophe (9/11 is a perfect example) will develop psychological after-effects known as post-traumatic stress syndrome or disorder – sometimes called PTSD. Some of the main symptoms of this are nightmares and flashbacks, avoiding situations or even thoughts that might recall the event, and irritability, including outbursts of anger. People may also experience physical symptoms like sweating, dizziness, or rapid heart rate when reminded of the traumatic experience. Several studies have found some of these symptoms, but not the full-blown disorder, in parents of children who have been treated for cancer.
How this study was done: In a change from earlier studies where parents were examined after the child had been treated, this study looked at parents while their child was still in active treatment. The parents (119 mothers and 52 fathers) of 125 children undergoing cancer therapy were given questionnaires about their psychological state. The results of these were compared with a measure of the intensity of their child's therapy.
What was found: About 68% of mothers and 57% of fathers had moderate to severe symptoms of post-traumatic stress. These didn't seem to be related to the intensity of their child's treatment. Mothers were more severely affected than fathers, with more symptoms of intrusive thoughts, avoiding reminders of the treatment, and more irritability, perhaps even anger. These results were compared with those of previous studies that looked at other parents after their child’s treatment had been completed and found that parents' symptoms were worse during treatment.
The bottom line: The study authors say health care providers need to be aware of the effect cancer treatments and tests may have on the psychological health of the parents. Parents should be counseled on how to deal with the stress of their child's treatment and taught when to seek more extensive professional help.
"We hope these findings will help mothers and fathers understand it's normal to have stress symptoms in reaction to their children's cancer," said psychologist Melissa Alderfer, PhD, a co-author of the current study. "Parents need to take care of themselves to they can be more helpful to their children."
Citation: "Posttraumatic stress symptoms during treatment in parents of children with cancer." Published in the Oct. 20, 2005, Journal of Clinical Oncology (Vol. 23, No. 30: 7405-7410). First author: Anne E. Kazak, PhD, ABPP, the Children's Hospital of Philadelphia.