Lynch syndrome, the most common hereditary colon cancer disorder, increases the risk of colorectal cancer (CRC) as well as cancers of the endometrium, ovaries, pancreas and bile duct. Both the syndrome and associated cancers are usually caused by germline mutations in one of four mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2.
MMR genes identify and repair single nucleotide mismatches that occur as cells grow and divide; defects in these genes allow mutations to accumulate in cells, increasing the chance of malignancy.
Identifying people who are high risk — and distinguishing them from those who aren't — is important for their initial and subsequent care as well as the care of family members. A Lynch diagnosis may determine the extent of colon cancer surgery, for instance, and it increases the need for more-frequent colonoscopies after a colon cancer diagnosis.
The larger issue is cancer control. Lynch syndrome cancers can often be prevented with annual or biennial colonoscopies, beginning around age 20 or 10 years before the earliest age of diagnosis in the family. For these reasons, academic medical centers screen all new CRC and endometrial cancer patients for the disease.
Douglas L. Riegert-Johnson, M.D., a gastroenterologist and medical geneticist at Mayo Clinic in Jacksonville, Fla., says about 2 out of every 100 screened patients will test positive for Lynch syndrome and each of them will have, on average, two other family members with CRC or other Lynch-associated cancer.
In the initial screening, tumor tissue is evaluated through molecular microsatellite instability (MSI) or immunohistochemistry (IHC) testing. MSI looks for faulty replication of repetitive nucleotide chains in the DNA of tumor cells. IHC detects the presence or absence of protein products expressed by mismatch repair genes.
IHC, commonly used at Mayo Clinic, is about 95 percent accurate, identifying in most people the MMR gene in which either a germline mutation or somatic alteration that silences gene expression occurs. Patients with a positive tumor test are then offered targeted molecular genetic testing, which involves both DNA sequencing and exonic or whole-gene deletion studies.
Until very recently, this analysis was performed using Sanger sequencing at a cost of around $1,000 per gene. But in April 2013, Mayo Clinic introduced a hereditary colon cancer multigene panel that uses next-generation sequencing and array comparative genomic hybridization to evaluate for germline mutations in 17 genes associated with CRC development.
The panel provides a comprehensive evaluation for hereditary colon cancer in high-risk patients and can also serve as a second-tier test when previous targeted gene analysis is negative. Initial cost for the panel is expected to be $3,000 to $4,000.
Dr. Riegert-Johnson notes that a few other centers are using multigene panels for hereditary colon cancer but that, in general, far too little Lynch syndrome screening takes place. "As of today, 1 percent of hospitals — 57 of 5,724 — are listed as routinely screening for Lynch syndrome," he says. "Despite an important 2005 study supporting screening, it has been slow to catch on."
In fact, a study published in the April 2012 issue of the Journal of Clinical Oncology found that only 42 percent of all responding centers reported conducting any routine Lynch syndrome screening and fewer than three-quarters of comprehensive cancer centers did.
Dr. Riegert-Johnson notes, "Tumor testing should be the standard of care for several reasons. Screening for Lynch is one. It's also possible tests for faulty DNA mismatch repair genes can help predict response to chemotherapy in stage II colon cancer. patients with tumors similar to those seen in Lynch syndrome may not benefit from chemotherapy. It's a controversial idea and hasn't been proved prospectively, but it is currently under investigation in the ECOG 5202 clinical trial.
Kastrinos, et al. Screening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For? Journal of Clinical Oncology. 2012; 30:1024.