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Lynch syndrome
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Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), is characterised as a hereditary syndrome with a high probability of certain cancers including gastro-intestinal and gynecological cancers.[1]
Introduction
LS is a genetically heterogeneous autosomal dominant disease caused by inherited mutations of so-called mismatch repair (MMR) genes which include any of the following four DNA mismatch repair genes i.e.
- MLH1
- MSH2
- MSH6
- PMS2
It can also be caused by a deletion in the EPCAM gene which leads to methylation of the adjacent MSH2 promoter. MLH1 and MSH2 account for most cases of LS associated cancers - MLH1 for 50% of cases and MSH2 for 40% of cases.[1]
More than one thousand unique mutations have been reported for MLH1 and MSH2 genes and it appears that truncating mutations are the most frequent cause of deficient MMR function. Truncating mutations account for 68% of mutations found in MLH1 and for 82% of mutations found in MSH2.[2]
Diagnosis
Clinically LS is characterised by a high risk for early-onset colorectal cancer (CRC) and endometrial cancer. It also carries a moderate risk for urinary tract, ovarian, small bowel, stomach, pancreatic, biliary tract and brain cancers. LS is under-recognised and accounts for 1 - 3% of all colorectal cancers seen in the general population. LS is the cause of 8% of newly diagnosed CRCs in patients under the age of 50 years. LS is usually only identified due to family or personal histories of multiple and/or early-onset cancers. However, it is important to note that to make a definitive diagnosis of LS only requires a finding of a pathogenic variant in the MMR or EPCAM gene by molecular testing – no clinical findings or family history criteria are required.[1][3][4][5]
Clinical criteria used to identify suitable candidates for genetic/molecular testing of Lynch syndrome includes the use of Amsterdam I or Amsterdam II criteria - family history-based criteria - used to identify individuals likely to be mutation carriers, as well as the Bethesda guidelines - criteria to determine which individuals with CRC should be tested for microsatellite instability (MSI) - as CRC tumors in Lynch syndrome demonstrate evidence of high MSI.[4]
LS cancer incidences
Based on a multicenter study of mainly European countries, Møller et al. reported calculated cumulative incidence for any cancer at age 70 years according to gender to be 75% in females 58% in males respectively.[1] A Dutch study noted high cumulative risks of the 2 commonest cancers seen in LS, namely CRC and endometrial cancer at 60%-80% and 30%-50% respectively and a Finnish study quoted the lifetime risk for CRC in LS patients of 70%-80% in the absence of preventive surveillance.[3][6]
Women with LS have a higher risk of cancer compared to men with LS due to the sex-specific increased risk of endometrial and ovarian cancer.[1][6] See figure 1 below.
Estimates for future cancer risk in LS mutation carriers vary greatly according to age and mutation type as shown by figure 2 below.
Calculated cumulative incidences for any cancer from 25, 40, 50 and 60 to 70 years of age for LS patients by mutated gene, without prior or prevalent cancer at first colonoscopy.[1]
It is estimated that LS germline mutations in PMS2 are the most prevalent, followed by mutations in MSH6, MLH1 and MSH2. Mutations in MLH1 and MSH2 however carry the highest risk of developing CRC. Cancer risks in individuals with a pathogenic EPCAM variant are like those with a pathogenic MSH2 variant.[4] Figure 3 to 6 below show the lifetime risks of the most prevalent LS cancers by mutated gene, age, and gender.[1]
Calculated cumulative cancer incidence to given age by group and mutated gene.[1]
Surveillance in LS
International consensus on guidelines for screening LS mutation carriers appears has not yet been established but most guidance suggests colonoscopy every 1 to 3 years for early detection of CRC. Ideally, individuals with LS, with MLH1 or MSH2 mutations, should undergo CRC screening with annual colonoscopy beginning at age 20 to 25 years, or two to five years prior to the earliest age of CRC diagnosis in the family (whichever comes first). LS carriers with either MSH6 or PMS2 mutations can delay the onset of CRC screening until age 30 to 35 years.[3][5][7][8]
Gynecological examinations to screen for early detection of endometrial cancer in females is recommended.[5] Endometrial cancer has excellent five-year and ten-year survival and despite the lack of robust evidence some guidelines recommended that women with LS undergo regular pelvic examination and endometrial biopsy.[1][5]
For other cancers related to LS, there are no evidence-based effective screening modalities available.[3][5][6]
Image: Graphicroyalty - stock.adobe.com
Prophylactic surgery
Risk-reducing hysterectomy and bilateral salpingo-oophorectomy surgery is effective in preventing endometrial and ovarian cancers in women with LS and is recommended when childbearing is complete.[3][5] In contrast, prophylactic colectomy for mutation carriers who have an endoscopically normal colon is not routinely recommended. Studies comparing the efficacy of endoscopic surveillance and prophylactic colectomy in preventing CRC are lacking. Prophylactic colectomy is reserved for patients who are unable or unwilling to undergo routine CRC surveillance.[5]
Metachronous CRC in LS
LS patients have a high incidence of metachronous colorectal cancer - a second primary cancer that develops months or years after a first primary cancer. Therefore, many experts recommend an extensive surgical approach such as total or subtotal colectomy when colorectal cancers is diagnosed. Data from one large study of colorectal cancer in LS showed the cumulative incidence of CRC to be 16% at 10 years and 62% at 30 years after segmental colectomy compared to 0% after extensive colectomy.[3][9]
This finding was confirmed by Kim et al. in a study published in 2016 that showed the risk of metachronous CRC to be significantly higher in patients who underwent a segmental colonoscopy compared to those who had an extensive colectomy despite intensive surveillance by annual endoscopy. They found that most metachronous CRCs presented with early-stage disease. The authors also reference a study that found the 10-year cumulative risk of metachronous CRC to be 4.6 times reduced following a subtotal colectomy compared to a segmental colectomy.[9]
Mortality considerations in LS with a cancer history
The two major LS-associated cancer types i.e. colorectal cancer and endometrial cancer have good observed survival. This is thought to be due to several factors including:
- Early detection due to surveillance
- Improved prognosis due to detection at early stages
- High degree of immunogenicity of LS cancers
- More favorable pathological and molecular genetic tumor characteristics
- Paucity of progressive metastatic disease in LS colorectal cancers
- Efficacy of current available treatments [1][6][7]
MMR gene mutations seen in LS result in cancers with microsatellite instability (MSI), a feature which is not often seen in sporadic cancers. This feature appears to give LS patients with CRC significantly better survival when compared to patients with sporadic CRC. Some of the mechanisms by which MSI colorectal cancers result in improved survival is thought to be due to:
- Increased T-cell infiltration of these tumors - implying these LS-related CRC tumors are highly immunogenic.
- Reduced tumor cell viability in LS-related CRC tumors due to genomic instability [10]
Survival rates for upper GI and urinary tract cancers were significantly worse compared to colorectal, endometrial cancers.[1] De Jong et al. showed that the standardised mortality ratios for extracolonic LS-related cancers including small bowel, brain, kidney, ovarian and stomach were significantly increased.[6] In a Finnish study only 7.9% of LS-related cancer deaths were from CRCs whereas 61% of deaths were due to extra-colonic and extra-endometrial cancers.[3] In the study by Kim et al. 40% of the cancer deaths were due to extra-colonic cancers.[9]
Fig. 7: 5 & 10 yr Crude Survival after 1st cancer diagnosis in LS patients without prior cancer at 1st colonoscopy [1]
Underwriting considerations
LS, also known as hereditary non-polyposis colorectal cancer, is an under-recognised monogenic adult-onset disorder that can result in several different types of cancers due to mutations found in the so-called DNA mismatch repair genes. It is generally regarded as an uninsurable condition but with our improved genomic and molecular understanding of the disorder, this risk can now be considered for life insurance with careful consideration of the applicant’s age, gender, LS mutation type and previous cancer history.
Author
Nico van Zyl MBBCh MSc
VP & Chief Medical Director
Hannover Life Reassurance Company of America
November 2024
References
- Møller P et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017; 66:464-472
- Janavicius R et al. Novel germline MSH2 mutation in Lynch Syndrome patient surviving multiple cancers. Hereditary Cancer in Clinical Practice 2012, 10:1
- Pylvanainen K et al. Causes of death of mutation carriers in Finnish Lynch syndrome families. Familial Cancer (2012) 11:467–471
- Hall MJ et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis. https://www.uptodate.com. Accessed 7/11/2024
- Jarvinen HJ et al. Ten Years After Mutation for Lynch Syndrome: Cancer Incidence and Outcome in Mutation-Positive and Mutation-Negative Family Members. J Clin Oncol October 2009, 27:4793-4797
- De Jong AE et al. Decrease in Mortality Syndrome Families Because of Surveillance. Gastroenterology 2006;130:665–671
- De Vos tot Nederveen Cappel WH et al. Colorectal surveillance in Lynch syndrome families. Familial Cancer (2013) 12:261-265
- Hall MJ et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer Screening and Management. https://www.uptodate.com. Accessed 10/11/2024
- Kim TJ et al. Surgical Outcome and Risk of Metachronous Colorectal Cancer after Surgery in Lynch Syndrome. Annals of Surgical Oncology (2017) 24:1085-1092
- Drescher KM et al. Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients. Clinical and Developmental Immunology; Vol 2010, Article ID 170432, 13 pagesUdd B, Meola G, Krabe R, et al., “Myotonic Dystrophy Type 2 (DM2 and Related Disorders: Report of the 180th ENMC Workshop Including Guidelines on Diagnostics and Management 3-5 December 2010, Naarden, The Netherlands”, Neuromuscul Disord, 2011; 21:443-450.
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