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MMR genes (Lynch syndrome) – risk management

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Lynch syndrome is an autosomal dominant condition caused by germline pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 or a deletion in EPCAM affecting MSH2 function.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Known mismatch repair (MMR) gene pathogenic variant carrier
  • Individuals at 50% risk of being a MMR gene pathogenic variant carrier

Exclusion criteria

  • Individuals from families fulfilling Amsterdam I or II clinical criteria with active exclusion of MMR defect by tumour testing or where no molecular tumour testing or germline testing is possible
  • Familial gastric cancer syndrome
  • Individuals with a tumour showing loss of functional MMR pathway but in whom no germline MMR pathogenic variant has been identified after testing, and their first-degree relatives
  • Individuals with a variant of uncertain significance.
Cancer/
tumour type		 MLH1 to age
70 years		 MSH2 to age 
70 years		 MSH6 to age
70 years		 PMS2 to age
70 years		 Lynch syndrome 
to age 70 years		 General
population
to age 70 years*
Colorectal
(male)		 53%r** 46%r** 12%r** up to 20%r**# 38% 3.0%
Colorectal
(female)		 44%r** 42%r** 20%r** up to 15%r**# 31% 2.1%
Endometrial 35%r 47%r 41%r 13%r 33% 1.3%
Gastric 6%r 4%r 1%r - 6% 0.37%
Ovarian 11%r 17%r 11%r 3%r 9% 0.5%
Urothelial## 7%r 21%r 7%r - <3% 0.34%
Small bowel 0.4%r 1.1%r Insufficient
data 		 - <3% 0.14%
Prostate 7%r 16%r 5%r 5%r - 8.1%

Note: there is no clinically relevant increased risk of breast cancerrr

* Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/. (2016 data)
** This data does not take into account the impact of surveillance
# Risk depends on family history
## Mainly ureteric and renal pelvis cancers but can include bladder cancer

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk.

The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/
tumour type		 Recommendations
Colorectal Surgical Consider subtotal colectomy in selected individuals
  Age  Strategy and frequency
Surveillance
MLH1/MSH2		 From age 25 yearsr
  • Colonoscopy every 1 to 2 years
Surveillance
MSH6/PMS2		 From age 35 yearsr
  • Colonoscopy every 1 to 2 years
  • Review frequency of colonoscopy at age 60 years with a view to reducing frequency
Risk-reducing medication Unless contraindicated, aspirin should be actively considered to reduce the risk of colorectal cancer. A low dose (100–300 mg per day) is recommended from the commencement of colonoscopy screening
Endometrial Surgical
MLH1/MSH2/MSH6		 Recommend hysterectomy after childbearing complete or from age 40 years
Surgical 
PMS2		 Recommend hysterectomy after childbearing complete or from age 50 years
Surveillance There is no evidence for transvaginal ultrasound (TVU) and/or aspiration biopsy
Ovarian Surgical
  • Consider risk-reducing salpingo-oophorectomy (RRSO) at time of risk-reducing hysterectomy
  • Recommend menopausal hormone therapy (MHT) at the time of RRSO and continue until the usual time of menopause
Surveillance Do not offer serum CA125 and/or transvaginal ultrasound (TVU). See Cancer Australia for further information
Gastric Surveillance
  • Consider 2nd yearly gastroscopy from age 30 years in families with gastric cancer or those at high ethnic risk e.g. Chinese, Korean, Chilean and Japanese
  • Screen for Helicobacter pylori and gastritis
Urothelial Surveillance No evidence of benefit but patients encouraged to report symptoms e.g. haematuria
Prostate Surveillance There is insufficient evidence regarding prostate cancer surveillance in Lynch syndrome

Management of early menopause

Specialist advice regarding the use of menopausal hormone therapy (MHT) after oophorectomy is recommended. There is no conclusive data regarding an increased risk of breast cancer in Lynch syndrome.

Colorectal cancer

Surgical

Subtotal colectomy reduces the chance of a second primary colon cancer but has not been shown to have a survival advantage.r People who are not having regular colonoscopies are most likely to benefit.  

Surveillance

Since MSH6 and PMS2 pathogenic variant carriers have a lower risk of colorectal cancer (CRC) and the age at diagnosis is later than in patients with MLH1 and MSH2 pathogenic variants, start screening at 35 years in MSH6 and PMS2 carriers, unless an early-onset cancer exists in a given family.rr

A study of 114 Lynch syndrome families comparing outcomes of screening at intervals of <2 years with >2 years demonstrated CRCs were diagnosed at a higher stage with the longer interval surveillance. Evidence supports screening every 1 to 2 years.rr

Since 57% of the neoplasms in Lynch syndrome occur proximal to the splenic flexure,r visualisation to the caecum is essential. 

Risk-reducing medication 

Considerable evidence supports the effectiveness of aspirin as risk-reducing medication for CRC in high risk Lynch syndrome patients (35-40% reduction in CRC risk). The benefit appears five years after starting aspirin and persists for at least 20 years. While there is limited evidence about the optimal dose and starting age, regular daily low-dose aspirin could be considered.r

Endometrial cancer

Surgical 

Hysterectomy is the only proven intervention which significantly reduces the risk of endometrial cancer.r 

Surveillance

There is no evidence to support a survival benefit from transvaginal ultrasound (TVU) and aspiration biopsy.r If surveillance is offered, it should be done in the context of a clinical trial.r

Ovarian cancer

Surgical

Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of developing ovarian cancer in pathogenic variant carriers.r Disease-free survival for ovarian cancers in patients with Lynch syndrome appears higher than for BRCA-associated ovarian cancer. Most ovarian cancers are diagnosed in pre-menopausal women and prognosis is generally good.r However, pre-menopausal women experience greater adverse effects from this surgery.r The risk of ovarian cancer is highest in MLH1, MSH2 and MSH6 pathogenic variant carriers suggesting they would benefit more from surgery than PMS2 carriers. Individualised risk is therefore based on the pathogenic variant, personal preference and family history.

Surveillance

Data extrapolated from other high-risk groups demonstrates annual TVU and serum CA125 levels have low sensitivity and specificity for ovarian cancer, and do not reliably detect ovarian cancers at an early stage, nor do they affect outcomes. This is true of women in the general population and women at high risk of hereditary ovarian cancer.r

Ovarian cancer risk management relies on risk-reducing salpingo-oophorectomy (RRSO - removal of the ovaries and fallopian tubes). See Cancer Australia for further information.

Gastric cancer

Surveillance

There is no evidence supporting the role of gastroscopy in the surveillance for gastric cancer in Lynch syndrome patients.r However, gastroscopy should be considered in families at high risk of gastric cancer.r There is a suggestion that chronic immune gastritis may play a role in the development of gastric cancer in individuals with Lynch syndrome, so an evaluation for gastritis and Helicobacter pylori infection could be considered.r

Urothelial transitional cell carcinoma 

Surveillance

There is no evidence for the role of urine cytology in the surveillance of urothelial carcinomas in MMR gene carriers. One study of individuals with confirmed or suspected Lynch syndrome demonstrated urine cytology had a sensitivity for malignancy of only 29%.r

Prostate cancer

Surveillance

In the general population, surveillance can be associated with over-diagnosis and over treatment with no evidence for improved short-term survival (ten year period). Surveillance for prostate cancer may be beneficial in situations where individuals have an increased risk of developing aggressive, early onset cancer. There is insufficient evidence regarding the characteristics of the prostate cancers seen in Lynch syndrome and therefore the role of prostate cancer surveillance in Lynch syndrome is unclear.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Bibliography

Abe Y., Mitsushima T, Nagatani K, et al 1995 "[Epidemiological evaluation of the protective effect for dying of stomach cancer by screening programme for stomach cancer with applying a method of case-control study--a study of a efficient screening programme for stomach cancer]"Nippon Shokakibyo Gakkai Zasshi. May;92(5):836-45.

An epidemiological evaluation of the protective effect for dying of stomach cancer by screening programme for stomach cancer was conducted with applying a method of case-control study. And also in order to carry out an efficient screening programme, the age groups who should be intensively recommended to receive screening and an optimal screening time interval since the last test were analyzed. 527 cases of men and 273 of women, dying of stomach cancer in the years 1981-1989 in the Awa region of Chiba prefecture, were identified from Chiba Cancer Registry. For each case, 3 controls were drawn at random from Awa living residents (about 162000 inhabitants at 1989 national census), with being matched strictly according to the district of residence, sex and born within 3 years of birth-year. For both cases and controls, the information about the screening history until the date of diagnosis of the case in each matched set was collected respectively from comparison with the screening certification. The results showed a relative risk of 0.417 (99% CI 0.284-0.612) in ever screened men compared with never screened and 0.480 (99% CI 0.280-0.823) in women. The significant reduction in risk was intensively observed on age groups 40-74 years among men and 50-69 years among women and the protective effect continued at most in the following three years since last screening. For an efficiency of screening programme, these age groups should be intensively recommended to receive screening and it is allowable that an optimal screening time interval since last negative test is at most 3 years for general attendance.

Alishahi S, Byrne D, Goodman CM, et al 2002 "Haematuria investigation based on a standard protocol: emphasis on the diagnosis of urological malignancy." J R Coll Surg Edinb. 2002 Feb;47(1):422-7.

To audit the findings of a standard investigation protocol for haematuria with emphasis on the diagnosis of urological malignancy. METHODS: Data were prospectively collected on haematuria referrals to one centre over a 5 year period. The standard protocol of investigation included flexible cystoscopy, urine cytology and culture, upper tract imaging, consisting of a renal tract ultrasound scan and a radiograph of kidney-ureter-bladder (KUB), proceeding to an intravenous urogram (IVU) in selected patients. RESULTS: 1046 patients were examined; 63% (n = 657) had microscopic haematuria and 37% (n = 389) had frank haematuria. No malignancy was found in patients with microscopic haematuria below 50 years of age. The findings of malignancy were not associated with either the sex or duration of symptoms in either groups. No association between the presence of symptoms and the finding of malignancy was observed in the microscopic haematuria group. Twenty five percent of patients presenting with frank haematuria had malignancy compared with 3.7% of patients with microscopic haematuria (p < 0.0001). The type of haematuria (frank or microscopic) was not predictive of grade or stage of malignancy. Of patients under 70 years with frank haematuria, males were more likely than females to have malignancy. This higher risk was not observed in older patients. Urine cytology had a poor predictive value for detection of malignancy with a sensitivity of only 25%. CONCLUSION: Full investigation of all patients with frank haematuria and those with microscopic haematuria above 50 years of age, is well justified. Patients under 50 years with microscopic haematuria should have a lower priority for investigation.

Dunlop, M. G., S. M. Farrington, A. D. Carothers, et al. 1997. "Cancer risk associated with germline DNA mismatch repair gene mutations." Hum Mol Genet 6(1):105-110.

The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying individuals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.

Evans, D. G., K. N. Gaarenstroom, D. Stirling, et al. 2009. "Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers." J Med Genet 46(9):593-597.

AIM: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk. PATIENTS AND METHODS: A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. RESULTS: 64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant. CONCLUSION: Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

Fukao A, Tsubono Y, Tsuji I, 1995 "The evaluation of screening for gastric cancer in Miyagi Prefecture, Japan: a population-based case-control study." Int J Cancer. Jan 3;60(1):45-8.

Although a screening program for gastric cancer, using barium X-ray examination, has been carried out widely in Japan for the past 3 decades, there is insufficient evidence to confirm its effectiveness in terms of reducing mortality. To evaluate the effectiveness of the screening, a population-based case-control study was carried out in Miyagi Prefecture, Japan. Case subjects, who had died from gastric cancer (198) and control subjects matched in age, sex and residence (577) were selected from among members of the National Health Insurance. Their screening histories during 5 years before the cases were diagnosed were surveyed on the basis of records of the regional cancer registry and the cancer-detection center. The odds ratio (OR) of death from gastric cancer for the persons who participated in the screening at least once during 5 years was 0.41. For those who participated only once during 5 years the OR was 0.43, and for those whose last participation was 5 years earlier it was 0.30. Our data suggest that screening for gastric cancer at 5-year intervals might reduce mortality by 60%, and that the effect might remain for at least 5 years.

Gaarenstroom, K. N., B. van der Hiel, et al. (2006). "Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study." Int J Gynecol Cancer 16 Suppl 1: 54-9.

The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.

Geary J., Sasieni P., Houlston R., et al. 2008. "Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)." Fam Cancer 7(2):163-172. Epub 2007 Oct 2016.

The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.

Lin KM, Shashidharan M, Ternent CA, et al 1998 "Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population." Dis Colon Rectum. Apr;41(4):428-33

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P < 0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P < 0.001, P = 0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1 vs. 28 percent MSH2; P = 0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P = 0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P = 0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P = 0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P < 0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P = 0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.

Oshima A, Hirata N, Ubukata T, 1986 "The evaluation of screening for gastric cancer in Miyagi Prefecture, Japan: a population-based case-control study." Int J Cancer. Dec 15;38(6):829-33.

In order to evaluate the effectiveness of a mass screening program for stomach cancer, a case-control study was conducted in Nose town in Osaka, Japan. The case series consisted of all deaths from stomach cancer during the period 1969-1981 (54 in males and 37 in females). For each case, 3 controls of the same sex and from the same precinct as the case, and born within 5 years of the case birth-year, were selected at random from Nose town residents alive at the date of death of the relevant case. We then investigated whether each case and corresponding controls had ever had screening tests before the date of diagnosis of the case. From the matched analysis of the distribution of screening in case-control combination, the odds ratio of screened vs. unscreened among those who died from stomach cancer compared to those who did not was calculated as 0.595 (90% confidence interval: 0.338-1.045) among males and 0.382 (0.185-0.785) among females. When the screening tests conducted within 12 months of diagnosis were ignored on the presumption that they were symptom-related, the odds ratio was calculated as 0.519 (0.297-0.905) among males and 0.486 (0.239-0.986) among females. These data strongly suggest that the mass screening program is effective in reducing stomach cancer mortality.

Rijcken FE, Mourits MJ, Kleibeuker JH, et al 2003 "Gynecologic screening in hereditary nonpolyposis colorectal cancer." Gynecol Oncol. Oct;91(1):74-80.

In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program. METHODS: Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files. RESULTS: Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected. CONCLUSIONS: These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance.

Schmeler KM., Lynch HT., Chen LM et al. 2002. "Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families." Dis Colon Rectum. 45(12):1588-1594.

PURPOSE: Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. METHODS: The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. RESULTS: A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8-17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1-27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. CONCLUSION: There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.

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.

BACKGROUND & AIMS: Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. METHODS: We studied 147 families with mismatch repair gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 US cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. RESULTS: We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%-76.17%) for men and 42.71% (95% CI, 36.57%-52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%-46.94%) with an overall HR of 39.0 (95% CI, 30.4-50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%-80.54%). CONCLUSIONS: Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.

Tsubono Y, Hisamichi S. 2000 "Screening for gastric cancer in Japan." Gastric Cancer. Aug 4;3(1):9-18.

In Japan, mass screening for gastric cancer with photofluorography was initiated in 1960. At present, over 6 million people are screened annually. The sensitivity and specificity of photofluorography are 70%-90% and 80%-90%, respectively. The 5-year survival rate is 15%-30% better in screen-detected cancers than in symptom-diagnosed cases. Although no randomized controlled trials have been reported, cohort and case-control studies generally showed a decreased risk of mortality from gastric cancer in the screened subjects. The summary odds ratio (95% confidence interval) of three case-control studies for ever screened versus never screened subjects was 0.39 (0.29-0.52) for men and 0.50 (0.34-0.72) for women. Substantial evidence indicates that the Japanese screening program with photofluorography is effective in reducing the mortality from gastric cancer. The measurement of serum pepsinogens has recently drawn attention as an alternative to photofluorography, given its lower cost and simplicity. Some studies have suggested a comparable accuracy for the two methods. However, these investigations may have overestimated the relative sensitivity of serum pepsinogen testing compared with photofluorography, because serum pepsinogen testing was conducted as prevalent screening, while photofluorography was done as incident screening. Furthermore, no studies have directly examined whether the screening with serum pepsinogens reduced gastric cancer mortality. Therefore, at present, evidence is insufficient to determine the benefit of this program.

Version 11

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Summary:
    • Template sentence updated
  • Target population:
    • Added to exclusion criteria "Individual with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated
    • Lifestyle factors sentence moved above the table.
  • Management of associated health problems:
    • Accordion title changed to "Management of associated health issues".

Version number increased to V.11.

Version 10

Date Summary of changes
13/08/2021

Protocol reviewed at August 2020 cancer genetics reference committee meeting. Discussion continued electronically via email and MS Teams. Approved for publication with the following changes made:

  • Related pages: link to 'Cancer predisposition genes: population carrier frequency' added
  • Target group: minor wording changes
  • Lifetime risk of cancer table:
    • Heading changed to 'Lifetime risk of cancer/tumour'
    • Figures revised and new references added
    • Risk for general population updated to include AIHW 2016 data
    • Prostate cancer added to table
    • Footnotes to table added
      • 'There is no clinically relevant increased risk of breast cancer'
      • 'Risks depend on family history'
      • 'Mainly ureteric and renal pelvis cancers but can include bladder cancer'
  • Cancer risk management guidelines:
    • Heading changed to 'Cancer/tumour risk management guidelines'
    • Sentence added above table 'The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.' 
    • Colorectal - Surveillance - MSH6: 'From age 25–30 years' changed to 'From age 35 years'
    • Ovarian - Surgical: 'Consider risk reducing salpingo-oophorectomy (RRSO) at time of hysterectomy in selected individuals.' changed to 'Consider risk-reducing salpingo-oophorectomy (RRSO) at time of risk-reducing hysterectomy'
    • Ovarian - Surveillance: link to Cancer Australia updated
    • Gastric - Surveillance: 'Screen for Helicobacter pylori and gastritis' added
    • Prostate - Surveillance: added to table
  • Management of associated health problems: 'HRT (hormone replacement therapy)' changed to 'MHT (menopausal hormone therapy)'
  • Evidence: 
    • Colorectal cancer - Surveillance update to align with changes in cancer risk management table
    • Colorectal cancer - Risk-reducing medication: paragraph updated and new reference added
    • Ovarian cancer - Surgical: paragraph updated to include evaluation for H. pylori and gastritis and new reference added
    • Prostate cancer - Surveillance: paragraph added
  • Support and information: template wording updated

Version number increased to V.10. Review in 2 years.
25/05/2022

Frequency of colonoscopy in Lynch syndrome discussed at March 2022 cancer genetics reference committee meeting. RC consensus to keep colonoscopy frequency at 1 to 2 years. Document updated with the following changes made:

  • Cancer/tumour risk management guidelines
    • Colorectal - Surveillance - MLH1/MSH2: 
      • Removed 'Annual surveillance is preferred in known pathogenic variant carriers'
      • Removed 'Review frequency of colonoscopy at age 60 years with a view to 2nd yearly frequency.'
    • Colorectal - Surveillance - MSH6/PMS2:
      • Removed 'Annual surveillance is preferred in known pathogenic variant carriers'
  • Evidence for risk management guidelines
    • Colorectal - Surveillance: references for 'Evidence supports screening every 1 to 2 years' updated to Herzig et al. 2017 and NCCN guidelines Genetics/Familial High-Risk Assessment Colorectal version 2, 2021.

Review at next scheduled review date. 

Version 9

Date Summary of changes
18/12/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.9.

Version 8

Date Summary of changes
18/10/2009 Approved
20/07/2010 Reviewed
14/02/2013

Discussed at April 2012 reference committee meeting and the following changes made:

  • New protocol number allocated ID 1410.
  • Target group - updated point 3 moved to exclusion criteria, point 4 updated and moved to exclusion criteria.
  • Exclusion criteria - updated as above.
  • Lifetime risk of cancer table updated.
  • Cancer risk management guidelines - reformatted in line with current template and updated.
  • Management of associated health problems - management of early menopause added.
  • Evidence for risk management guidelines - reformatted in line with current template and updated.
  • References reviewed, updated and previous references used to develop this protocol moved to history tab.
29/08/2013

Frequency of review discussed at March 6, 2013 reference committee meeting and discussion continued via email: 

  • Review yearly
31/07/2015 Link to AGSA changed to Genetic Alliance Australia.
09/08/2015

Protocol reviewed at October 23 2014 reference committee meeting and discussions continued via email:

  • Summary updated
  • Lifetime risk of cancer table - updated to list MMR genes (ACI 314 'Table of lifetime risk of cancer per gene' removed).
  • Cancer risk management guidelines table:
    • colorectal surveillance updated.
    • endometrial surgical updated.
    • ovarian surgical and surveillance updated.
  • Evidence for risk management guidelines:
    • colorectal cancer surveillance updated.
    • ovarian cancer surveillance updated.
  • References updated.
07/01/2016 Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016 Sentence added to risk management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up". 
31/05/2017 Transferred to new eviQ website. Version number changed to V.4.
21/03/2018 

Protocol reviewed and presented at the May 2017 eviQ Cancer Genetics Reference Committee meeting. Discussion continued over email and document approved for publication with the following changes: 

  • Lifetime risk of cancer statistics updated as per more recent papers.
  • Version number change to V.5. 
  • References updated. 
29/03/2019

Protocol underwent minor review and was presented at Nov 2018 RCM. Discussion continued over email and approved with the following changes made:

  • Summary: Sentence added from updated RM template.
  • Lifetime risk of cancer: statistics updated.
  • Cancer risk management guidelines: Recommendations updated to align with more recent data/publications.
  • Evidence for risk management guidelines: Updated to reflect updated cancer risk management guidelines.
  • References: updated.

Version changed to V.6 as updates signal practice change. Protocol to undergo major review at next scheduled date.
17/06/2019

Cancer risk management guidelines section:

  • Colorectal - risk reducing medication: Recommendation updated to actively consider low-dose aspirin from commencement of colonoscopy screening.

Version changed to V.7. as update to protocol signals practice change. Review date kept same.
28/08/2019 Protocol title changed from 'Risk management for Lynch syndrome' to 'MMR genes (Lynch syndrome) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.8.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1410

31 Mar 2023