Additional Resources

HT Lynch, PM Lynch, SJ Lanspa, CL Snyder, JF Lynch  and CR Boland (2009) Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications, Clinical Genetics, 76: 1- 18 

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (∼30,700 cases) willhave Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes(most frequently MLH1 or MSH2) and screening for CRC. Colonoscopyis mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age),colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40and then annually thereafter. Should CRC occur, subtotal colectomy maybe necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only10–25% of familial CRC.

Lindor, N. (2014) Lynch syndrome 101 (years, that is). Am Soc Clin Oncol Educ Book, 27-32

Lynch syndrome was described over a century ago but information on the medical consequences and optimal management of this disorder continue to amass and evolve. This brief overview highlights the gene-specific and site-specific cancer penetrance and management options for those with Lynch syndrome.

Møller, T. Seppälä, I. Bernstein, et. al. (forthcoming) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. December 2015. doi: 10.1136/gutjnl-2015-309675. 

OBJECTIVE: Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.

DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.

RESULTS: 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.

CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Win AK1, Lindor NM, Young JP,et al (2012) Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 Sep 19;104(18):1363-72.

BACKGROUND: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.

METHODS: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.

RESULTS: Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).

CONCLUSION: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

Tan YY, Spurdle AB, Obermair, A (2014) Knowledge, Attitudes and Referral Patterns of Lynch Syndrome: A Survey of Clinicians in Australia, Journal of Personalised Medicine, 4(2): 2018-244

This study assessed Australian clinicians’ knowledge, attitudes and referral patterns of patients with suspected Lynch syndrome for genetic services. A total of 144 oncologists, surgeons, gynaecologists, general practitioners and gastroenterologists from the Australian Medical Association and Clinical Oncology Society responded to a web-based survey. Most respondents demonstrated suboptimal knowledge of Lynch syndrome. Male general practitioners who have been practicing for ≥10 years were less likely to offer genetic referral than specialists, and many clinicians did not recognize that immunohistochemistry testing is not a germline test. Half of all general practitioners did not actually refer patients in the past 12 months, and 30% of them did not feel that their role is to identify patients for genetic referral. The majority of clinicians considered everyone to be responsible for making the initial referral to genetic services, but a small preference was given to oncologists (15%) and general practitioners (13%). Patient information brochures, continuing genetic education programs and referral guidelines were favoured as support for practice. Targeted education interventions should be considered to improve referral. An online family history assessment tool with built-in decision support would be helpful in triaging high-risk individuals for pathology analysis and/or genetic assessment in general practice.

Movahedi M, Bishop DT, Macrae F. et al (2015) Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study. Journal of Clinical Oncology

PURPOSE: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS).

PATIENTS AND METHODS: Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months.

RESULTS: During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m(2) increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03).

CONCLUSION: Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.

 The following 20 research papers are articles on which the Cancer Institute NSW has relied in developing the EviQ screening guidelines.

1. Baglietto, L., N. M. Lindor, J. G. Dowty, et al. 2010. “Risks of Lynch syndrome cancers for MSH6 mutation carriers.” J Natl Cancer Inst 102(3):193-201
2. Balmana, J., D. H. Stockwell, E. W. Steyerberg, E. M. Stoffel, A. M. Deffenbaugh, J. E. Reid, B. Ward, T. Scholl, B. Hendrickson, J. Tazelaar, L. A. Burbidge and S. Syngal. 2006. “Prediction of MLH1 and MSH2 mutations in Lynch syndrome.” JAMA 296(12):1469-1478
3. Barrow, P., M. Khan, F. Lalloo, D. G. Evans and J. Hill. 2013. “Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome.” Br J Surg 100(13):1719-1731
4. Bonadona, V., B. Bonaiti, S. Olschwang, et al. 2011. “Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.” JAMA 305(22):2304-2310
5. Capper, D., A. Voigt, G. Bozukova, A. Ahadova, P. Kickingereder, A. von Deimling, M. von Knebel Doeberitz and M. Kloor. 2013. “BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer.” Int J Cancer 133(7):1624-1630
6. Castillejo, A., E. Hernandez-Illan, M. Rodriguez-Soler, et al. 2015. “Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.” J Med Genet 52(7):498-502
7. Chen, S., W. Wang, S. Lee, K. Nafa, J. Lee, K. Romans, P. Watson, S. B. Gruber, D. Euhus, K. W. Kinzler, J. Jass, S. Gallinger, N. M. Lindor, G. Casey, N. Ellis, F. M. Giardiello, K. Offit, G. Parmigiani and Registry Colon Cancer Family. 2006. “Prediction of germline mutations and cancer risk in the Lynch syndrome.” JAMA 296(12):1479-1487
8. Dove-Edwin, I., A. E. de Jong, J. Adams, et al. 2006. “Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome.” Gastroenterology. 130(7):1995-2000.
9. Hampel, H., W. L. Frankel, E. Martin, et al. 2005. “Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).” N Engl J Med 352(18):1851-1860.
10. Koornstra, J. J. 2012. “Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome.” Best Pract Res Clin Gastroenterol 26(3):359-368
11. Mecklin JP., Aarnia M., Laara E et al 2006 “Development of Colorectal Tumors in Colonoscopic Surveillance in Lynch Syndrome” Gastroenterology Vol 133(4)1093-1093
12. Myrhoj, T., M. B. Andersen and I. Bernstein. 2008. “Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer.” Fam Cancer 7(4):303-307.
13. Schmeler, K. M., H. T. Lynch, L. M. Chen, et al. 2006. “Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.” N Engl J Med 354(3):261-269.
14. Schofield, L., F. Grieu, J. Goldblatt, et al. 2012. “A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours.” Fam Cancer 11(1):1-6.
15. Schofield, L., J. Goldblatt and B. Iacopetta. 2011. “Challenges in the diagnosis and management of Lynch Syndrome in an Indigenous family living in a remote West Australian community.” Rural Remote Health 11(4):1836.
16. Senter, L., M. Clendenning, K. Sotamaa, et al. 2008. “The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.” Gastroenterology 135(2):419-428
17. Stoffel, E., B. Mukherjee, V. M. Raymond, et al. 2009. “Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome.” Gastroenterology 137(5):1621-1627.
18. Vasen HF., Moslein G., Alonso A., et al 2007. “Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).” J Med Genet. 44(6):353-362. Epub 2007 Feb 2027.
19. Vasen, H. F., P. Watson, J. P. Mecklin, et al. 1999. “New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.” Gastroenterology 116(6):1453-1456
20. Weissman, S. M., R. Burt, J. Church, et al. 2012. “Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.” J Genet Couns 21(4):484-493