Over the past several years, awareness of the importance of hereditary cancer risk assessment has increased rapidly. Knowing whether a patient has an underlying genetic risk can be immensely helpful in guiding a patient’s medical management. Although the focus has been on the BRCA genes and breast cancer, Lynch syndrome poses a similar risk for colon cancer.
In 1966, Dr. Henry Lynch formally described a unique pattern of cancers known through the years as either Lynch syndrome or Hereditary Non-Polyposis Colorectal Cancer (HNPCC). 1 Lynch syndrome occurs in 1/300 people in the general population and accounts for 2-5% of all colorectal cancers.2,3 Individuals with Lynch syndrome have significantly elevated risks for colon/rectal, endometrial, ovarian, gastric, small bowel, hepatobiliary, skin, brain, pancreas and other cancers. A mutation in any one of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2 may lead to the spectrum of cancers seen with Lynch syndrome.4,5
In recent years, the focus has shifted from identifying patients based on their personal and family history (using tools such as the Bethesda and Amsterdam criteria), to relying on tumor testing results (IHC and/or MSI). Tumor testing provides a means to screen all patients with colorectal cancer. Significant limitations of tumor testing include a false negative rate of up to 17%,6 a lack of clinical follow through on abnormal results (sharing of the tumor results with patient, obtaining informed consent, completion of germline testing), and a loss of opportunity for making a fully informed surgical decision.
Impact on surgery
For patients who present with a diagnosis of colon cancer, knowing genetic risk status can significantly impact the surgical decision. Among patients with Lynch syndrome, the risk for a second colorectal cancer is nearly 20% within 10 years, and up to 69% by 30 years, following the initial cancer diagnosis.6
In response to this risk, the American Society of Colorectal Surgeons has issued the following guideline statement: “Colectomy with ileorectal anastomosis is the primary treatment for patients with Lynch syndrome who already have a diagnosis of colon cancer. Patients over age 60, or those with underlying sphincter dysfunction may prefer less aggressive surgical intervention”.7 Additionally, prophylactic hysterectomies and bilateral salpingo-oopherectomies can reduce the incidence of endometrial and ovarian cancer respectively for women with Lynch syndrome and are recommended for surgical consideration based on National Comprehensive Cancer Network (NCCN) guidelines.
Unfortunately, patients with Lynch syndrome are often not diagnosed until after surgery has already been completed. Relying on results of tumor testing for patient identification virtually guarantees that patients will not be identified in time for this guideline recommendation to be considered. Patients are likely to receive partial rather than total colectomies, leaving these patients at greatly elevated risk for future cancers. Using a combined approach including both the clinical evaluation of personal and family history with follow up universal tumor testing can lead to a more complete identification of individuals with Lynch syndrome, with results available at a time when critical decisions are being made.
Identifying Lynch Syndrome
NCCN has criteria for evaluating patients who may potentially have Lynch syndrome (which may include genetic testing), which are:
• Known Lynch syndrome mutation in the family
• Personal history of colorectal or endometrial cancer diagnosed before age 65
• Multiple synchronous or metachronous Lynch syndrome-related cancers1
• At least 1 first degree or second degree relative with Lynch syndrome-related cancer diagnosed before age 50
• At least 2 first degree or second degree relatives with Lynch syndrome-related cancers regardless of age
• At least 3 first degree or second degree relatives with Lynch syndrome-related cancers at any age
• Colorectal or endometrial cancer with high MSI/IHC histology
• PREMM5 score of 2.5% or higher
Myriad will process tests for any patient with colorectal cancer diagnosed before age 659
1. Lynch HT, et al. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1966;117(2):206–12.
2. Boland CR and Shike M. Report from the Jerusalem workshop on Lynch syndrome-Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 2010;138:2197.e1-e7
3. Chen S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479–87.
4. Weissman SM, et al. Genetic counseling considerations in the evaluation of families for Lynch syndrome-a review. J Genet Couns 2011 Feb;20(1):5-19. Epub 2010 Oct 8.
5. Barnetson RA, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006;354:2751-63.
6. Recommendations from the EGAPP working group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Evaluation of the Genomic Applications in Practice and Prevention (EGAPP) Working Group Genetics in Medicine 2009;11:35-41.
7. Win AK, et al. Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol 2013 Jun;20(60:1829-1836.
8. Herzig DO et al. Clinical practice guidelines for the surgical treatment of patients with Lynch syndrome. Dis Colon Rectum 2017;60:137-143.
9. Some exceptions apply (e.g. government payers)