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The Personalized Medicine Foundation collaborated with the Dana-Farber Cancer Institute to provide individuals with an opportunity to engage with a hereditary cancers expert, Kimberly Perez, M.D. on Lynch Syndrome. ​

What is Lynch Syndrome?

Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is the most common type of hereditary colon cancer. Five percent of colon cancers fall under Lynch syndrome; 1 in 300 to 400 people has the condition. In Lynch Syndrome the risk of cancer is very high; lifetime risk can be as high as 80 percent, and cancers often occur at a younger age—many occurring before age 40 and even before age 30.

When a patient is determined, through genetic testing or a clinical diagnosis to have Lynch syndrome, other family members should be notified so that they can be tested to see if they also carry the mutation. This topic can be sensitive, but distributing this information can save lives. A diagnosis of Lynch syndrome can greatly impact the medical management of an individual even if they have already had a diagnosis of cancer; however, the bigger benefit is to all the at risk relatives who don’t have cancer and with genetic counseling and testing can begin a cancer screening protocol to prevent or detect cancers at an early and treatable stage.

Individuals with Lynch Syndrome are also at risk for cancers developing in uterus, ovary, pancreas and urinary tract

Cancer Screening & Early Detection

I have Lynch Syndrome and get regular colonoscopies; can these be replaced by the new blood test or stool test for colon cancer?

Dr. Perez: Unfortunately, the study published for which this modality of testing was approved did not include persons with high risk of colorectal cancer or Lynch syndrome. There have been no follow up prospective studies comparing the use of the new blood test or stool test for colon cancer screening in the Lynch syndrome population.

If you have Lynch syndrome, should you start screening at 10 years younger than your relative’s age when they had cancer or just start at 35?

Dr. Perez: The recommendations suggest to start screening at 20-25 years of age (if genetic test is positive or diagnostic of Lynch syndrome) or 2-5 years prior to first affected relative.

I have Lynch Syndrome and take Celebrex for arthritis. Is this as good as aspirin for prevention? If not, how much Aspirin is typically recommended per day?

Dr. Perez: The only completed study that evaluated the benefit of aspirin as a preventative medication in Lynch syndrome patients evaluated 600mg of Aspirin and compared it to placebo. Initial results did not show a clinical benefit but in long term follow up there is some suggestion that persons who took it for greater than 2 years did see a potential benefit. The other issue which has been identified is that the single dose of Aspirin used is a higher dose than the dose used for daily cardioprotective benefits and it is unclear if that higher dose is necessary. Therefore, a follow up study evaluating various lower doses is being conducted, which we have open for enrollment at our center, which is trying to address this question of dose and overall impact on colorectal health in persons with Lynch syndrome.

Genetic Testing

I am a mother of 2 kids, ages 13 and 11, and I have Lynch syndrome. What age should my kids get tested?

Dr. Perez: They should get tested or consider testing between the ages of 20-25. That being said, every young adult is different and the ability to process the implications of testing is different for each person. If there are any questions or concerns about having your children tested seek out the support and guidance of a local cancer genetics genetic counselor and/or clinician.

Is there more than one genetic mutation that causes Lynch syndrome and how do you test to know which one you have?

Dr. Perez: There is more than one genetic mutation. There are actually 5 genes [MLH1, MSH2, MSH6, PMS2, or EPCAM] that have been identified which if mutated would carry a diagnosis of Lynch syndrome. Within each of the 5 genes, multiple mutations have been identified in the gene sequence that are diagnostic for Lynch syndrome as well. It is best to discuss testing options with a genetic counselor or provider.

Some of my relatives, including several aunts, have Lynch syndrome, but my father does not. Is it still possible that I have inherited it?

Dr. Perez: It is not possible for you to have inherited a Lynch syndrome associated mutation from your father. This can be explained by the fact that your father did not inherit/carry the Lynch syndrome associated mutation that his sisters carry, and you are not a direct offspring of one of your aunts with Lynch syndrome, therefore there is no means of direct transmission of the genetic mutation to you.

I had uterine cancer. My father had kidney cancer, stomach cancer, bladder pre-cancer, non-melanoma skin cancer, & cancer of unknown primary on chest wall near lungs. His mother had stomach cancer and his brother had colon cancer. I had genetic testing- one gene result was inconclusive. I still am uneasy because one of the genes came back inconclusive- what does that mean?

Dr. Perez: Inconclusive means that we have not yet determined if the mutation is associated with or diagnostic of a hereditary cancer syndrome. Given your history and family history, I would recommend corresponding with your high-risk clinic or genetic counselor/provider every 1-2 years to reassess your risk, as with time we will learn more.

I had a sister pass away 4 years ago from gall bladder cancer. She was 47 years old. Nothing was tested. Two years ago, when I was 52, I was diagnosed with endometrial cancer and had a complete hysterectomy. My tumor was tested and I was diagnosed with Lynch syndrome. I had genetic testing done but they couldn’t determine the exact mutation so no one else in my family could be tested. Is this common? I have an identical twin sister and we were told that she should also take precautions.

Dr. Perez: There are people with tumor testing that suggests Lynch syndrome who then have genetic testing that does not identify a mutation in one of the mismatch repair genes. In 30-40% of cases, further testing demonstrates a non-genetic abnormality (a.k.a. an acquired genetic abnormality) that can explain this finding. In this scenario, clinical surveillance would follow one outlined for persons with average lifetime risk of colorectal cancer. In 60-70% of persons in this scenario, no other molecular cause is identified and we designate this group as Lynch-like syndrome. It appears that the average age of diagnosis of cancer is similar to those with Lynch syndrome, however the lifetime risk of cancer development is not necessarily the same, and may actually be lower, than those with Lynch syndrome.

With that being said, since we as a scientific community are still investigating this Lynch-like syndrome, standard guideline clinical surveillance for Lynch syndrome associated cancers/tumors should be initiated.

I have recently been diagnosed with Lynch syndrome – PMS2. I can find lots of information about Lynch syndrome, but most give stats and information related to MLH1 or MSH2 mutations. Can you point me to any information specific to the PMS2 mutation?

Dr. Perez: The National Cancer Institute and most of the commercial vendors who provide genetic testing platforms have informative information regarding PMS2 mutations specifically.

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Recent published studies which discuss PMS2 mutations and the associated clinical impact include the following:

  • Broeke S, et al. Lynch Syndrome caused by germline PMS2 Mutations: Delineating the cancer risk. Journal of Clinical Oncology. 2015 Feb 1; 33:319.
  • Goodenberger ML, et al. PMS2 monoallelic mutation carriers: the known unknown. Genetics in Medicine. 2016 Jan; 18(1): 13-9.

My husband was diagnosed with stage 4 colon cancer at age 47. We are not aware of any family history of cancer except lung cancer which was a result of his father smoking heavily. Our doctor suggests that my husbands’ colon cancer does not appear to be genetic, based on microsatellite instability (MSI) and his age. Should he have genetic testing? How accurate is genetic testing?

Dr. Perez: That is a tough question that is commonly asked. We currently stratify patients who should undergo genetic risk assessment and consideration for testing to patients who have particular clinical findings. There are limitations to our current diagnostic tools which include:

  • Tumor testing can be negative in a Lynch syndrome patient with an inherited genetic mutation.
  • Small families or early age of death in family members may limit our ability to adequately assess one’s risk and need for testing.
  • Tumor testing only evaluates patients for the risk of Lynch syndrome and not other hereditary syndromes that may increase ones’ risk of developing colon cancer.

If you or your husband would like to discuss this further, I would recommend going for a cancer genetics risk assessment and counseling with a licensed genetic counselor or experience clinician in the field. Even if he does not meet criteria for genetic testing, it is important to discuss colon cancer surveillance options that he can share with your extended family.

To learn more about the Dana-Farber Cancer Institute’s Center for Cancer Genetics and Prevention click here.

Ovarian and Uterine Cancer Risk

Do you think most doctors would recommend a complete hysterectomy for Lynch syndrome PMS2 mutation carriers who are done having kids but premenopausal and without a family history of ovarian cancer? My question is specifically directed toward ovarian cancer (OC) risk (understanding uterine cancer risk is higher). The OC risk appear to be “elevated” but generally speaking less than 6% by 70 years of age, which is lower than other Lynch mutations. Some European publications do not recommend oophorectomy given the low risk, but the U.S. genetic testing companies’ brochures seem to advise. Would your answer change if a patient had a personal history of hormone-sensitive breast cancer?

Dr. Perez: Women with Lynch syndrome are at a reported lifetime risk of 4-12% for ovarian cancer. Families that carry a mutation in PMS2 have not consistently followed the same degree of cancer risk as Lynch syndrome patients with mutations in MLH1 or MSH2.

So my answer would be consideration for oophorectomy and hysterectomy after child bearing age is reached. This should be considered since current screening modalities for ovarian cancer are not reliable. If oophorectomy and hysterectomy is not accepted as an option, then I would encourage the individual to follow with an experienced gynecologist for ovarian and uterine screening.

I would not factor in the hormone positive breast cancer into this decision. Discussion regarding the benefits of oophorectomy in a patient with hormone positive breast cancer should be taken up with the person’s oncologist. With that said I would not apply to a relative with Lynch syndrome.

What are the latest findings on the link between Lynch syndrome and uterine sarcoma?

Dr. Perez: Lynch syndrome is associated with uterine carcinomas. There have been case reports of persons with Lynch syndrome who have been diagnosed with a uterine sarcoma though it is uncommon. Since the link is not clear, if a woman presents with this type of tumor histology (uterine sarcoma) and has a past medical history and/or family history that suggest Lynch syndrome, I will typically recommend genetic testing.

My mother was diagnosed with colorectal cancer at age 75. I was diagnosed with endometrial cancer stage1/1A in 2010 with a recurrence in 2015. I discussed the possibility of Lynch syndrome with my oncologist and he told me that due to my mother having cancer later in life it most likely was not a possibility in my case. I am not aware of any other family members who have had cancer. I have two daughters and worry for them. Do you think I am a candidate for genetic testing?

Dr. Perez: Your candidacy would depend on a few factors. One, did your doctor have your endometrial tumor tissue tested for Lynch syndrome? Two, if tumor testing was negative and there is no other family history, based on the limited family history you have provided, no further testing would be indicated. If the situation is still leaving you with any concern, I would recommend continued discussion with your primary care doctor/team, or even a Cancer Genetics and Risk assessment consultation with a genetic counselor/provider.

I have Muir-Torre Syndrome and have had multiple skin cancers removed & many internal cancers removed, I am 73. Two of my children have the same syndrome and are facing their second internal cancers. How rare is our cancer syndrome, which falls under Lynch syndrome?

Dr. Perez: Muir-Torre syndrome is considered a rare Lynch syndrome variant. It was coined to describe individuals with a combination of sebaceous neoplasms and one or more Lynch-associated cancers. It is a rare, though shares a similar risk of other Lynch-associated cancers as it is associated with mutations in the MLH1 and MSH2 genes. Therefore, screening regimens would follow standard guidelines established for other persons with Lynch syndrome.

My father passed away from stomach cancer. My brothers and I were told we should get checked because this could be hereditary. Is this true and what type of tests other than the obvious should we undergo to see if we are in fact going to get this?

Dr. Perez: The risk of stomach cancer can be inherited. There is a 6-13% lifetime risk of stomach cancer associated with Lynch syndrome. There are other inherited syndromes that can increase ones’ risk of stomach cancer. BUT, not all stomach cancers are inherited. A great majority are acquired. If you are interested to discuss or determine your risk of an inherited syndrome, I would recommend that you discuss this with your primary care provider and/or seek consultation for cancer genetics risk assessment and counseling.

Risk of Genitourinary Cancer?

I have Lynch syndrome – long family history: mother, grandfather, etc. My mother is 65 and was diagnosed with cancer in her ureter last year, and her sister had the same thing the year before. This appears to be uncharted territory for people with Lynch syndrome, or maybe it’s just our family. We are having a hard time nailing down a good protocol for catching this. Our doctors don’t seem to know much about Lynch association with bladder cancer – is there any research or established protocol?

Dr. Perez: The National Comprehensive Cancer Network (NCCN) and other professional societies recommend annual urinalysis starting at age 25-30 years in carriers of MLH1, MSH2 or EPCAM mutations. In families with your description, we recommend regular follow up with a urologist to discuss and /or pursue cystoscopic surveillance.

Risk of Breast Cancer

There seems to be inconsistent data about whether breast cancer is related to Lynch syndrome. If a known Lynch syndrome patient has breast cancer at a young age, and an IHC test of the tumor shows loss of nuclear expression of the pathogenic gene, are there any studies that would shed light on either treatment of that breast cancer, or future risk or screenings (for example, MRIs in connection with mammograms)?

Dr. Perez: Despite the recent suggestions of an increased risk for breast cancer in persons with Lynch syndrome, the data thus far does not support increased screening above average risk breast cancer screening recommendations or any impact on breast cancer treatment.

Does being Lynch syndrome and BRAF positive lower a person’s rate of survival? Nobody talks about BRAF positive with Lynch /colon cancer.

Dr. Perez: The presence of a tumor BRAF gene mutation in association with tumor testing results that demonstrate microsatellite instability or loss of MLH1 or PMS2 supports the diagnosis of a sporadic or acquired colorectal cancer, not Lynch syndrome. BRAF mutations are present in approximately 15% of colorectal cancers, and very rare in Lynch syndrome associated colorectal tumors.

About Dr. Perez

Dr. Kimberly Perez is a Medical Oncologist at Dana-Farber Cancer Institute. She is a faculty member of the Gastrointestinal Disease Center and Center for Cancer Genetics and Prevention, and is part of the clinical faculty at Harvard Medical School. Dr. Perez attended medical school at the George Washington University School of Medicine in Washington, D.C., and completed her post-graduate training in Internal Medicine, Hematology and Oncology at Brown University Medical School. She recently joined the Dana-Farber faculty in November 2015, after 5 years of clinical practice as a GI oncologist at Rhode Island Hospital Comprehensive Cancer Center in Providence, to further develop her research and clinical interests in Gastrointestinal Cancer Care and Gastrointestinal Cancer Genetics.


The Ask The Expert Series is made possible by support fromThe Personalized Medicine Foundation, Incyte Oncology, Abbvie, and CancerConnect. The "Ask The Expert" series is not medical advice nor is it a substitute for your doctor. It should serve as a guide to facilitate access to additional information and enhancement of a shared decision making process with your treating physician.