bs_bs_banner
and expenditure in overweight and obese adults: a randomized controlled trial. Arch Intern Med 2009; 169: 2109–15. 50 Gardiner PA, Eakin EG, Healy GN, Owen N. Feasibility of reducing older adults’ sedentary time. Am J Prev Med 2011; 41: 174–7. 51 Fitzsimons CF, Kirk A, Baker G, Michie F, Kane C, Mutrie N. Using an
individualised consultation and activPAL feedback to reduce sedentary time in older Scottish adults: results of a feasibility and pilot study. Prev Med 2013; 57: 718–20. 52 Hill K, Dolmage TE, Woon L, Coutts D, Goldstein R, Brooks D. Defining the relationship between average daily energy expenditure and field-based
walking tests and aerobic reserve in COPD. Chest 2012; 141: 406–12. 53 Wasserman K, Hansen J, Sue D, Whipp B. Principles of Exercise Testing and Interpretation.Philadelphia, PA: Lippincott, Williams and Wilkins; 2005.
C L I N I C A L P E R S P E CT I V E S
Familial colorectal cancer M. S. Lung,1 A. H. Trainer,1,2,3 I. Campbell1 and L. Lipton3 1
Research Division and 2Familial Cancer Centre, Peter MacCallum Cancer Centre and 3Familial Cancer Centre, Royal Melbourne Hospital, Melbourne,
Victoria, Australia
Key words colorectal neoplasm, adenomatous polyposis coli, hereditary nonpolyposis, neoplastic syndrome, hereditary. Correspondence Lara Lipton, Familial Cancer Clinic, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia. Email: [email protected]
Abstract Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz–Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.
Received 27 August 2014; accepted 24 February 2015. doi:10.1111/imj.12736
Introduction Australia and New Zealand have the highest incidence rate of colorectal cancer (CRC) in the world, with an
Funding: M. S. Lung is funded by the Cancer Council of Victoria and The University of Melbourne. Conflict of interest: None. Abbreviations APC, adenomatous polyposis coli; CHRPE, congenital hypertrophy of the retinal pigment epithelium; CI, confidence interval; CRC, colorectal cancer; FAP, familial adenomatous polyposis; HHT, hereditary haemorrhagic telangiectasia; HR, hazard ratio; IHC, immunohistochemistry; JPS, juvenile polyposis syndrome; LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability; OR, odds ratio; PJS, Peutz–Jeghers syndrome.
age-adjusted rate of 46 per 100 000 men and 32 per 100 000 women in 2008.1 The risk of developing CRC by age 85 is 1 in 10 for men and 1 in 15 for women.2 Approximately 30% of the risk of sporadic CRC is thought to be due to inherited genetic factors.3 Conversely, hereditary CRC syndromes with a known highrisk genetic aetiology make up approximately 5% of CRC. Such disorders include Lynch syndrome (LS), familial adenomatous polyposis (FAP), MUTYH-associated neoplasia and the hamartoma syndromes (Table 1). Identification of individuals and families with these syndromes allows the implementation of effective surveillance strategies which result in a reduction in cancer incidence and death in many cases. Here we discuss the genetics, clinical manifestations and management of the known familial CRC syndromes, © 2015 Royal Australasian College of Physicians
482
Familial colorectal cancer
Table 1 Summary of main familial colorectal cancer syndromes with associated genes and phenotypes Syndrome
Associated gene(s)
Lynch syndrome
MLH1, MSH2, MSH6, PMS2, EPCAM APC
Colonic phenotype
Major extra-colonic associations Endometrial, ovarian, gastric, small bowel, urinary tract, brain, biliary cancers; sebaceous gland tumours; keratoacanthomas Gastric fundic polyps; duodenal adenomas; papillary thyroid cancer; medulloblastomas; desmoids; osteomas Duodenal polyposis; other associations not fully defined
MUTYH-associated neoplasia Juvenile polyposis syndrome
MUTYH SMAD4, BMPR1A
CRC often R-sided; tends to be poorly-differentiated; mucinous/signet ring histology; lymphocytic infiltrate Multiple adenomatous polyps (10–1000 s) adenomatous polyps or CRC without adenomatous polyps Juvenile polyps
Peutz–Jeghers syndrome
STK11
Hamartomas
Classical FAP
and offer guidelines on whom to refer to a familial cancer clinic for risk assessment and potential genetic testing.
Lynch syndrome LS (hereditary non-polyposis CRC, HNPCC) is the most common inherited CRC syndrome, accounting for approximately 3% of all CRC diagnoses.4
Genetics LS is an autosomal dominant syndrome caused by a mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene, which is situated upstream of MSH2. Interestingly, EPCAM is not involved in MMR, but deletions in this gene indirectly cause abrogation of MSH2 function.5,6 Germline MLH1 and MSH2 mutations account for >80% of LS cases,7 MSH6 for up to 10%,7 PMS2 for 2–3% and EPCAM for 1–3%.8 It is likely that PMS2 mutations make a significant contribution to LS but the exact extent of this contribution is currently unclear because of difficulties in distinguishing genuine mutations in this gene from those present in numerous pseudogenes.9 The types of inactivating mutations in the MMR genes include frameshift, nonsense, splice site, missense/ in-frame deletions or genomic rearrangements which can occur throughout each gene.10,11 Amino acid altering missense mutations are more common in MLH1 than MSH2.12 Large deletions of the 3′ end of the EPCAM gene result in transcriptional read-through and epigenetic silencing of MSH2.5 Founder mutations have also been described such as an A→T transversion in the donor splice site of intron 5 of MSH2, which occurs in Newfoundland,13 but also occurs as a recurrent mutation worldwide and may account for up to 10% of LS cases.14
Juvenile polyps throughout gastrointestinal tract; increased risk of small bowel, stomach and pancreas cancers Hereditary haemorrhagic telangiectasia Mucocutaneous pigmentation Hamartomas throughout gastrointestinal tract; increased risk of breast, stomach, pancreatic and gynaecological cancers
LS tumours arise when the wild type copy of the gene is lost in the tumour, resulting in inactivation of the MMR pathway in the tumour. This causes an accumulation of errors in long repetitive stretches of DNA called microsatellites, resulting in alleles of differing lengths or ‘microsatellite instability’ (MSI).15,16 Genes with microsatellites in their coding region often undergo frameshift mutations in MSI tumours and include genes involved in cell proliferation, apoptosis and DNA repair such as TCF4, ILGFR-2, TGFBR2, AXIN2, BAX, PTEN, CHK1, MLH3, MSH3 and MSH6.17 In LS, cancers may harbour somatic mutations in KRAS and adenomatous polyposis coli (APC) but rarely BRAF.18
Clinical features and genotype-phenotype correlations Individuals with LS are at risk of developing CRC at an earlier age (median age 45)4 than the general population (median age 71). They have a varying risk to age 70 years of developing CRC which depends upon the gene that is mutated (Table 2). The majority (∼70%) of CRC develop proximal to the splenic flexure.20 CRC in LS tends to be poorly differentiated, have mucinous or signet ring histology and have a marked lymphocytic infiltrate.4 Female carriers of a LS mutation carry a 12–54% lifetime risk of endometrial cancer depending on the gene mutated and a risk of ovarian cancer between 1% and 38% (Table 1).10 Other LS-associated cancers include gastric cancer, small bowel adenocarcinoma, transitional cell carcinoma of bladder, ureters or renal pelvis, biliary tract cancer, glioblastomas (previously known as Turcot variant) and sebaceous gland tumours and
© 2015 Royal Australasian College of Physicians
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Lung et al.
Table 2 Cumulative cancer risk to age 70 years by mutation type in Lynch syndrome Mismatch repair gene mutation MLH110 MSH210 MSH610 PMS211 EPCAM19
CRC risk (%) 41 48 12 15–20 75
Endometrial cancer risk (%)
Ovarian cancer risk (%)
Gastric cancer risk (%)
Small bowel cancer risk (%)
Urinary tract cancer risk (%)
Brain cancer risk (%)
Biliary tract cancer risk (%)
54 21 16 15 12
20 38 1
6 0.2 0
0.4 1.1 0
0.2 2.2 0.7
≤3 ≤3 ≤3
1.9
keratoacanthomas (previously known as Muir–Torre variant).4,21 The risk of these cancers varies with the specific gene mutated.
Diagnosis of LS The revised Bethesda guidelines22 were developed to help clinicians decide on which CRC to test for MSI. These guidelines are highly sensitive but have poor specificity.23 The Amsterdam criteria24 have been used since prior to the discovery of MMR gene mutations to identify LS families.24 They remain highly specific for LS mutations (60–70%) but do not have the sensitivity to be used for population screening. Molecular testing of CRC using MSI or immunohistochemistry (IHC) for the four MMR proteins is used, where possible, to aid in choosing patients for Lynch syndrome genetic testing. The sensitivity of both methods is high and comparable.25 These tests are also useful in screening for LS in endometrial cancer.26 Certain caveats apply to IHC testing however. False negatives may occur if the protein is present but not functional, which can occur in the presence of germline pathogenic missense mutations.27 Also, 15% of sporadic CRC harbour somatic hypermethylation of the MLH1 promoter causing an MSI phenotype in the cancers with loss of MLH1 IHC and may therefore be mistaken for LS.28 These patients do not have LS and 40% of these CRC may harbour a V600E BRAF mutation that is very rare in LS.29 If a mutation is found in a MMR gene, predictive genetic testing can be offered to unaffected family members before the age at which screening should commence.
Surveillance and management CRC surveillance in LS reduces CRC-related mortality,30,31 is estimated to increase life expectancy by 7 years32 and is cost-effective.32 There is non-randomised, controlled trial evidence that three yearly colonoscopies reduce incidence and mortality from CRC in LS33; however, level IIIC evidence
favours 1–2-year intervals between colonoscopies due to the rapid adenoma to carcinoma development in LS and this is the standard practice in Australia.4,34–36 LS mutation carriers should start surveillance colonoscopy at the ages of 25 or 5 years prior to the earliest diagnosis of CRC in the family, whichever is younger.36 There is no recommended age at which surveillance colonoscopies should be stopped. Guidelines based on expert consensus regarding the management of LS34 suggest that screening for extracolonic cancers should ideally be done as part of a clinical trial as no direct evidence for reduction in mortality from screening is available. Prophylactic hysterectomy and bilateral salpingo-oopherectomy is recommended for female mutation carriers when they have completed their families and reached the age of 40 years34 as no effective surveillance exists for ovarian or endometrial cancer.37,38 For patients with a family history of gastric cancer or those from a high-risk background (Chinese, Korean, Japanese, Chilean), second yearly gastroscopy may be considered.
Surgical management of CRC in LS When a LS mutation carrier develops CRC, several factors need to be considered when deciding between a partial colectomy and a subtotal colectomy. The risk of interval cancers on surveillance colonoscopies post partial colectomy is between 6% and 35%.34 However, no difference in 10-year survival was seen in a retrospective cohort study of 382 patients who underwent either extended colectomy or a segmental resection for their first CRC, despite a metachronous CRC rate of 0% in those who had an extended colectomy versus 22% for those who had a segmental resection.39 In a separate study, quality of life did not differ significantly between 23 patients who had a segmental operation compared with 27 patients who had extended surgery.40 Both the European Society of Medical Oncology 2013 familial CRC guidelines36 and the LS management guidelines by the Mallorca group34 recommend discussing the option of an extended colectomy with a © 2015 Royal Australasian College of Physicians
484
Familial colorectal cancer
LS patient with CRC. Factors including patient wishes, family planning and likely adherence to close follow-up colonoscopic surveillance should be considered.
Chemoprevention The Colorectal Adenoma/Carcinoma Prevention Program 2 trial randomised over 1000 individuals with known or suspected LS to 600 mg per day of aspirin for 2 years versus placebo.41 The study’s primary end-point was development of colorectal adenoma or carcinoma. There was no difference in the incidence of colorectal adenomas or carcinomas between the two groups at a mean follow-up time of 27 months. At a mean follow up of 55.7 months, the hazard ratio (HR) for developing CRC in the aspirin group was 0.63 (95% confidence interval (CI) 0.35–1.13, P = 0.12) on an intention-to-treat analysis. In the subgroup of patients who completed 2 years of 600 mg aspirin, the HR was 0.41 (95% CI 0.19–0.86, P = 0.02) compared with the placebo group. There was also a trend to a decrease in non-CRC LS cancers, with the group of patients who completed 2 years of aspirin having a HR of 0.47 (95% CI 0.21–1.06, P = 0.07). Adverse events did not differ while on treatment; however, data were not collected on post-intervention adverse effects. The ongoing Colorectal Adenoma/Carcinoma Prevention Program 3 trial is determining the optimal dose of aspirin.
Constitutive MMR deficiency Constitutive mismatch repair deficiency, a rare autosomal recessive condition, has been described primarily in the paediatric population.42 The inheritance of biallelic MMR gene mutations results in lack of competent MMR in all tissues. Individuals develop haematological malignancies and rare brain tumours such as gliomas in childhood as well as LS-associated tumours and café au-lait spots.43 It can also present with colonic polyposis suggestive of attenuated FAP or MUTYH-associated neoplasia.44 This condition is diagnosed on IHC for MMR proteins, and demonstrates absent MMR staining in both tumour and surrounding normal tissue.
Familial adenomatous polyposis Classical FAP results in the development of hundreds to thousands of polyps in the colon and/or rectum by the time of adolescence. Untreated, FAP results in CRC in ∼100% of cases by the fourth decade.45 Seventy to eighty per cent of these CRC are left sided.46 FAP occurs in 1 in 8000–10 000 individuals and accounts for 5000 polyps).48 Mutations in codon 1309 result in an earlier onset of CRC at a mean age of 35 years.49 Mutations at or beyond codon 1444 confer an 11-fold increase in risk of developing desmoids.50 Mutations between exons 9 and 15 (codons 311 to 1444) are associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), which is the commonest extra-intestinal manifestation of FAP.49 Once a pathogenic mutation in the APC gene is found, presymptomatic genetic screening can be offered to blood relatives. An attenuated form of FAP is associated with mutations in the 5′ end, exon 9 and 3′ ends of the APC gene.51–53 This group of patients generally has a delayed appearance of colonic adenomas and CRC by around 10–20 years.54 In clinically determined attenuated FAP, with 30–100 polyps, an APC mutation is found in 30% of cases.55
Extra-intestinal manifestations of FAP FAP is associated with gastric fundic gland polyps and duodenal adenomas, duodenal cancer, papillary thyroid cancer (rare), hepatoblastoma in childhood (rare) and central nervous system tumours (predominantly medulloblastoma). Non-malignant associations include desmoid tumours, CHRPE,56 epidermoid skin cysts and osteomas (Gardner syndrome), lipomas and adrenal tumours (very rarely malignant).56 CHRPE associated with FAP tends to manifest as multiple bilateral lesions with a depigmented halo.57 The main causes of death in FAP patients following colectomy are duodenal cancer and desmoid tumours.58 Desmoid tumours are locally aggressive connective tissue tumours that do not have metastatic potential. They usually occur in the abdominal wall or mesentery or in an abdominal surgical scar, and may cause morbidity and mortality due to small bowel obstruction, ischaemia or
© 2015 Royal Australasian College of Physicians
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Lung et al.
perforation, intra-abdominal abscesses and fistulas, or ureteric obstruction.56
Surveillance and management Since the advent of molecular diagnosis and prophylactic surveillance and surgery, the mortality from CRC in FAP has decreased significantly.59 For known APC mutation carriers and at risk relatives from families where a clinical diagnosis has been made but in which mutation testing is not possible, two yearly flexible sigmoidoscopy should start at the age of 12–14 years of age.36 Yearly colonoscopy should be done when polyps are seen and continued until colectomy.36 Colectomy is usually performed in late adolescence or early adulthood. Surgical options are proctocolectomy with ileal pouch-anal anastomosis in individuals with a high rectal polyp burden or total colectomy with ileorectal anastomosis. Those with a retained rectum require annual endoscopy post-colectomy. For attenuated FAP cases, two yearly colonoscopy is recommended rather than sigmoidoscopy, starting at the age of 18–20 years,36 as adenomas are found throughout the colon. Screening for extra-intestinal manifestations of FAP should begin at diagnosis or at the age of 25–30 years, whichever is earlier.36 Upper gastrointestinal endoscopy using both front- and side-viewing endoscopy is performed every 5 years until the detection of adenomas. The frequency of upper endoscopies once adenomas are detected depends on the Spigelman stage of the polyps,60 which takes into account polyp number, size, histology and dysplasia. Symptomatic desmoid tumours may be treated with medical therapy including non-steroidal antiinflammatory drugs with tamoxifen or raloxifene61 and with chemotherapy.62 Surgical manipulation may result in disease progression and should only be undertaken by specialist surgeons after multidisciplinary consultation.36
Chemoprevention Small trials have suggested that ascorbate,63 sulindac64 and the COX-2 inhibitors65 may result in a reduction in adenoma burden of 10–40% while on treatment.66 Some patients had regression of their adenomas; however, the adenomas recurred when treatment was stopped. The Concerted Action Polyp Prevention 1 trial did not find any effect on polyp number with the use of aspirin or resistant starch. Aspirin is not currently used for chemoprevention of FAP.
MUTYH-associated neoplasia MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome that results in the development of several to hundreds of colorectal polyps and/or CRC67 and can present in a similar manner to FAP. MUTYH is an important differential diagnosis in individuals with presumed de novo FAP, and genetic testing is the only means to differentiate between these two conditions, which have significantly different clinical implications to relatives of the affected individual. While the association of MUTYH gene mutations with hereditary CRC was first defined in patients with colorectal polyposis,67,68 subsequent population-based CRC studies have found that up to one third of patients with biallelic MUTYH mutations develop CRC without additional polyps being identified at the time of diagnosis.69,70 Hence MUTYH-associated CRC is not invariably associated with colorectal polyposis and is a diagnosis that should be considered in young onset CRC irrespective of polyp status. Patients with biallelic mutations in MUTYH have a 93-fold increased risk of CRC although this figure is subject to ascertainment bias.71 MAP is associated with duodenal polyposis (
and expenditure in overweight and obese adults: a randomized controlled trial. Arch Intern Med 2009; 169: 2109–15. 50 Gardiner PA, Eakin EG, Healy GN, Owen N. Feasibility of reducing older adults’ sedentary time. Am J Prev Med 2011; 41: 174–7. 51 Fitzsimons CF, Kirk A, Baker G, Michie F, Kane C, Mutrie N. Using an
individualised consultation and activPAL feedback to reduce sedentary time in older Scottish adults: results of a feasibility and pilot study. Prev Med 2013; 57: 718–20. 52 Hill K, Dolmage TE, Woon L, Coutts D, Goldstein R, Brooks D. Defining the relationship between average daily energy expenditure and field-based
walking tests and aerobic reserve in COPD. Chest 2012; 141: 406–12. 53 Wasserman K, Hansen J, Sue D, Whipp B. Principles of Exercise Testing and Interpretation.Philadelphia, PA: Lippincott, Williams and Wilkins; 2005.
C L I N I C A L P E R S P E CT I V E S
Familial colorectal cancer M. S. Lung,1 A. H. Trainer,1,2,3 I. Campbell1 and L. Lipton3 1
Research Division and 2Familial Cancer Centre, Peter MacCallum Cancer Centre and 3Familial Cancer Centre, Royal Melbourne Hospital, Melbourne,
Victoria, Australia
Key words colorectal neoplasm, adenomatous polyposis coli, hereditary nonpolyposis, neoplastic syndrome, hereditary. Correspondence Lara Lipton, Familial Cancer Clinic, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia. Email: [email protected]
Abstract Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz–Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.
Received 27 August 2014; accepted 24 February 2015. doi:10.1111/imj.12736
Introduction Australia and New Zealand have the highest incidence rate of colorectal cancer (CRC) in the world, with an
Funding: M. S. Lung is funded by the Cancer Council of Victoria and The University of Melbourne. Conflict of interest: None. Abbreviations APC, adenomatous polyposis coli; CHRPE, congenital hypertrophy of the retinal pigment epithelium; CI, confidence interval; CRC, colorectal cancer; FAP, familial adenomatous polyposis; HHT, hereditary haemorrhagic telangiectasia; HR, hazard ratio; IHC, immunohistochemistry; JPS, juvenile polyposis syndrome; LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability; OR, odds ratio; PJS, Peutz–Jeghers syndrome.
age-adjusted rate of 46 per 100 000 men and 32 per 100 000 women in 2008.1 The risk of developing CRC by age 85 is 1 in 10 for men and 1 in 15 for women.2 Approximately 30% of the risk of sporadic CRC is thought to be due to inherited genetic factors.3 Conversely, hereditary CRC syndromes with a known highrisk genetic aetiology make up approximately 5% of CRC. Such disorders include Lynch syndrome (LS), familial adenomatous polyposis (FAP), MUTYH-associated neoplasia and the hamartoma syndromes (Table 1). Identification of individuals and families with these syndromes allows the implementation of effective surveillance strategies which result in a reduction in cancer incidence and death in many cases. Here we discuss the genetics, clinical manifestations and management of the known familial CRC syndromes, © 2015 Royal Australasian College of Physicians
482
Familial colorectal cancer
Table 1 Summary of main familial colorectal cancer syndromes with associated genes and phenotypes Syndrome
Associated gene(s)
Lynch syndrome
MLH1, MSH2, MSH6, PMS2, EPCAM APC
Colonic phenotype
Major extra-colonic associations Endometrial, ovarian, gastric, small bowel, urinary tract, brain, biliary cancers; sebaceous gland tumours; keratoacanthomas Gastric fundic polyps; duodenal adenomas; papillary thyroid cancer; medulloblastomas; desmoids; osteomas Duodenal polyposis; other associations not fully defined
MUTYH-associated neoplasia Juvenile polyposis syndrome
MUTYH SMAD4, BMPR1A
CRC often R-sided; tends to be poorly-differentiated; mucinous/signet ring histology; lymphocytic infiltrate Multiple adenomatous polyps (10–1000 s) adenomatous polyps or CRC without adenomatous polyps Juvenile polyps
Peutz–Jeghers syndrome
STK11
Hamartomas
Classical FAP
and offer guidelines on whom to refer to a familial cancer clinic for risk assessment and potential genetic testing.
Lynch syndrome LS (hereditary non-polyposis CRC, HNPCC) is the most common inherited CRC syndrome, accounting for approximately 3% of all CRC diagnoses.4
Genetics LS is an autosomal dominant syndrome caused by a mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene, which is situated upstream of MSH2. Interestingly, EPCAM is not involved in MMR, but deletions in this gene indirectly cause abrogation of MSH2 function.5,6 Germline MLH1 and MSH2 mutations account for >80% of LS cases,7 MSH6 for up to 10%,7 PMS2 for 2–3% and EPCAM for 1–3%.8 It is likely that PMS2 mutations make a significant contribution to LS but the exact extent of this contribution is currently unclear because of difficulties in distinguishing genuine mutations in this gene from those present in numerous pseudogenes.9 The types of inactivating mutations in the MMR genes include frameshift, nonsense, splice site, missense/ in-frame deletions or genomic rearrangements which can occur throughout each gene.10,11 Amino acid altering missense mutations are more common in MLH1 than MSH2.12 Large deletions of the 3′ end of the EPCAM gene result in transcriptional read-through and epigenetic silencing of MSH2.5 Founder mutations have also been described such as an A→T transversion in the donor splice site of intron 5 of MSH2, which occurs in Newfoundland,13 but also occurs as a recurrent mutation worldwide and may account for up to 10% of LS cases.14
Juvenile polyps throughout gastrointestinal tract; increased risk of small bowel, stomach and pancreas cancers Hereditary haemorrhagic telangiectasia Mucocutaneous pigmentation Hamartomas throughout gastrointestinal tract; increased risk of breast, stomach, pancreatic and gynaecological cancers
LS tumours arise when the wild type copy of the gene is lost in the tumour, resulting in inactivation of the MMR pathway in the tumour. This causes an accumulation of errors in long repetitive stretches of DNA called microsatellites, resulting in alleles of differing lengths or ‘microsatellite instability’ (MSI).15,16 Genes with microsatellites in their coding region often undergo frameshift mutations in MSI tumours and include genes involved in cell proliferation, apoptosis and DNA repair such as TCF4, ILGFR-2, TGFBR2, AXIN2, BAX, PTEN, CHK1, MLH3, MSH3 and MSH6.17 In LS, cancers may harbour somatic mutations in KRAS and adenomatous polyposis coli (APC) but rarely BRAF.18
Clinical features and genotype-phenotype correlations Individuals with LS are at risk of developing CRC at an earlier age (median age 45)4 than the general population (median age 71). They have a varying risk to age 70 years of developing CRC which depends upon the gene that is mutated (Table 2). The majority (∼70%) of CRC develop proximal to the splenic flexure.20 CRC in LS tends to be poorly differentiated, have mucinous or signet ring histology and have a marked lymphocytic infiltrate.4 Female carriers of a LS mutation carry a 12–54% lifetime risk of endometrial cancer depending on the gene mutated and a risk of ovarian cancer between 1% and 38% (Table 1).10 Other LS-associated cancers include gastric cancer, small bowel adenocarcinoma, transitional cell carcinoma of bladder, ureters or renal pelvis, biliary tract cancer, glioblastomas (previously known as Turcot variant) and sebaceous gland tumours and
© 2015 Royal Australasian College of Physicians
483
Lung et al.
Table 2 Cumulative cancer risk to age 70 years by mutation type in Lynch syndrome Mismatch repair gene mutation MLH110 MSH210 MSH610 PMS211 EPCAM19
CRC risk (%) 41 48 12 15–20 75
Endometrial cancer risk (%)
Ovarian cancer risk (%)
Gastric cancer risk (%)
Small bowel cancer risk (%)
Urinary tract cancer risk (%)
Brain cancer risk (%)
Biliary tract cancer risk (%)
54 21 16 15 12
20 38 1
6 0.2 0
0.4 1.1 0
0.2 2.2 0.7
≤3 ≤3 ≤3
1.9
keratoacanthomas (previously known as Muir–Torre variant).4,21 The risk of these cancers varies with the specific gene mutated.
Diagnosis of LS The revised Bethesda guidelines22 were developed to help clinicians decide on which CRC to test for MSI. These guidelines are highly sensitive but have poor specificity.23 The Amsterdam criteria24 have been used since prior to the discovery of MMR gene mutations to identify LS families.24 They remain highly specific for LS mutations (60–70%) but do not have the sensitivity to be used for population screening. Molecular testing of CRC using MSI or immunohistochemistry (IHC) for the four MMR proteins is used, where possible, to aid in choosing patients for Lynch syndrome genetic testing. The sensitivity of both methods is high and comparable.25 These tests are also useful in screening for LS in endometrial cancer.26 Certain caveats apply to IHC testing however. False negatives may occur if the protein is present but not functional, which can occur in the presence of germline pathogenic missense mutations.27 Also, 15% of sporadic CRC harbour somatic hypermethylation of the MLH1 promoter causing an MSI phenotype in the cancers with loss of MLH1 IHC and may therefore be mistaken for LS.28 These patients do not have LS and 40% of these CRC may harbour a V600E BRAF mutation that is very rare in LS.29 If a mutation is found in a MMR gene, predictive genetic testing can be offered to unaffected family members before the age at which screening should commence.
Surveillance and management CRC surveillance in LS reduces CRC-related mortality,30,31 is estimated to increase life expectancy by 7 years32 and is cost-effective.32 There is non-randomised, controlled trial evidence that three yearly colonoscopies reduce incidence and mortality from CRC in LS33; however, level IIIC evidence
favours 1–2-year intervals between colonoscopies due to the rapid adenoma to carcinoma development in LS and this is the standard practice in Australia.4,34–36 LS mutation carriers should start surveillance colonoscopy at the ages of 25 or 5 years prior to the earliest diagnosis of CRC in the family, whichever is younger.36 There is no recommended age at which surveillance colonoscopies should be stopped. Guidelines based on expert consensus regarding the management of LS34 suggest that screening for extracolonic cancers should ideally be done as part of a clinical trial as no direct evidence for reduction in mortality from screening is available. Prophylactic hysterectomy and bilateral salpingo-oopherectomy is recommended for female mutation carriers when they have completed their families and reached the age of 40 years34 as no effective surveillance exists for ovarian or endometrial cancer.37,38 For patients with a family history of gastric cancer or those from a high-risk background (Chinese, Korean, Japanese, Chilean), second yearly gastroscopy may be considered.
Surgical management of CRC in LS When a LS mutation carrier develops CRC, several factors need to be considered when deciding between a partial colectomy and a subtotal colectomy. The risk of interval cancers on surveillance colonoscopies post partial colectomy is between 6% and 35%.34 However, no difference in 10-year survival was seen in a retrospective cohort study of 382 patients who underwent either extended colectomy or a segmental resection for their first CRC, despite a metachronous CRC rate of 0% in those who had an extended colectomy versus 22% for those who had a segmental resection.39 In a separate study, quality of life did not differ significantly between 23 patients who had a segmental operation compared with 27 patients who had extended surgery.40 Both the European Society of Medical Oncology 2013 familial CRC guidelines36 and the LS management guidelines by the Mallorca group34 recommend discussing the option of an extended colectomy with a © 2015 Royal Australasian College of Physicians
484
Familial colorectal cancer
LS patient with CRC. Factors including patient wishes, family planning and likely adherence to close follow-up colonoscopic surveillance should be considered.
Chemoprevention The Colorectal Adenoma/Carcinoma Prevention Program 2 trial randomised over 1000 individuals with known or suspected LS to 600 mg per day of aspirin for 2 years versus placebo.41 The study’s primary end-point was development of colorectal adenoma or carcinoma. There was no difference in the incidence of colorectal adenomas or carcinomas between the two groups at a mean follow-up time of 27 months. At a mean follow up of 55.7 months, the hazard ratio (HR) for developing CRC in the aspirin group was 0.63 (95% confidence interval (CI) 0.35–1.13, P = 0.12) on an intention-to-treat analysis. In the subgroup of patients who completed 2 years of 600 mg aspirin, the HR was 0.41 (95% CI 0.19–0.86, P = 0.02) compared with the placebo group. There was also a trend to a decrease in non-CRC LS cancers, with the group of patients who completed 2 years of aspirin having a HR of 0.47 (95% CI 0.21–1.06, P = 0.07). Adverse events did not differ while on treatment; however, data were not collected on post-intervention adverse effects. The ongoing Colorectal Adenoma/Carcinoma Prevention Program 3 trial is determining the optimal dose of aspirin.
Constitutive MMR deficiency Constitutive mismatch repair deficiency, a rare autosomal recessive condition, has been described primarily in the paediatric population.42 The inheritance of biallelic MMR gene mutations results in lack of competent MMR in all tissues. Individuals develop haematological malignancies and rare brain tumours such as gliomas in childhood as well as LS-associated tumours and café au-lait spots.43 It can also present with colonic polyposis suggestive of attenuated FAP or MUTYH-associated neoplasia.44 This condition is diagnosed on IHC for MMR proteins, and demonstrates absent MMR staining in both tumour and surrounding normal tissue.
Familial adenomatous polyposis Classical FAP results in the development of hundreds to thousands of polyps in the colon and/or rectum by the time of adolescence. Untreated, FAP results in CRC in ∼100% of cases by the fourth decade.45 Seventy to eighty per cent of these CRC are left sided.46 FAP occurs in 1 in 8000–10 000 individuals and accounts for 5000 polyps).48 Mutations in codon 1309 result in an earlier onset of CRC at a mean age of 35 years.49 Mutations at or beyond codon 1444 confer an 11-fold increase in risk of developing desmoids.50 Mutations between exons 9 and 15 (codons 311 to 1444) are associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), which is the commonest extra-intestinal manifestation of FAP.49 Once a pathogenic mutation in the APC gene is found, presymptomatic genetic screening can be offered to blood relatives. An attenuated form of FAP is associated with mutations in the 5′ end, exon 9 and 3′ ends of the APC gene.51–53 This group of patients generally has a delayed appearance of colonic adenomas and CRC by around 10–20 years.54 In clinically determined attenuated FAP, with 30–100 polyps, an APC mutation is found in 30% of cases.55
Extra-intestinal manifestations of FAP FAP is associated with gastric fundic gland polyps and duodenal adenomas, duodenal cancer, papillary thyroid cancer (rare), hepatoblastoma in childhood (rare) and central nervous system tumours (predominantly medulloblastoma). Non-malignant associations include desmoid tumours, CHRPE,56 epidermoid skin cysts and osteomas (Gardner syndrome), lipomas and adrenal tumours (very rarely malignant).56 CHRPE associated with FAP tends to manifest as multiple bilateral lesions with a depigmented halo.57 The main causes of death in FAP patients following colectomy are duodenal cancer and desmoid tumours.58 Desmoid tumours are locally aggressive connective tissue tumours that do not have metastatic potential. They usually occur in the abdominal wall or mesentery or in an abdominal surgical scar, and may cause morbidity and mortality due to small bowel obstruction, ischaemia or
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perforation, intra-abdominal abscesses and fistulas, or ureteric obstruction.56
Surveillance and management Since the advent of molecular diagnosis and prophylactic surveillance and surgery, the mortality from CRC in FAP has decreased significantly.59 For known APC mutation carriers and at risk relatives from families where a clinical diagnosis has been made but in which mutation testing is not possible, two yearly flexible sigmoidoscopy should start at the age of 12–14 years of age.36 Yearly colonoscopy should be done when polyps are seen and continued until colectomy.36 Colectomy is usually performed in late adolescence or early adulthood. Surgical options are proctocolectomy with ileal pouch-anal anastomosis in individuals with a high rectal polyp burden or total colectomy with ileorectal anastomosis. Those with a retained rectum require annual endoscopy post-colectomy. For attenuated FAP cases, two yearly colonoscopy is recommended rather than sigmoidoscopy, starting at the age of 18–20 years,36 as adenomas are found throughout the colon. Screening for extra-intestinal manifestations of FAP should begin at diagnosis or at the age of 25–30 years, whichever is earlier.36 Upper gastrointestinal endoscopy using both front- and side-viewing endoscopy is performed every 5 years until the detection of adenomas. The frequency of upper endoscopies once adenomas are detected depends on the Spigelman stage of the polyps,60 which takes into account polyp number, size, histology and dysplasia. Symptomatic desmoid tumours may be treated with medical therapy including non-steroidal antiinflammatory drugs with tamoxifen or raloxifene61 and with chemotherapy.62 Surgical manipulation may result in disease progression and should only be undertaken by specialist surgeons after multidisciplinary consultation.36
Chemoprevention Small trials have suggested that ascorbate,63 sulindac64 and the COX-2 inhibitors65 may result in a reduction in adenoma burden of 10–40% while on treatment.66 Some patients had regression of their adenomas; however, the adenomas recurred when treatment was stopped. The Concerted Action Polyp Prevention 1 trial did not find any effect on polyp number with the use of aspirin or resistant starch. Aspirin is not currently used for chemoprevention of FAP.
MUTYH-associated neoplasia MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome that results in the development of several to hundreds of colorectal polyps and/or CRC67 and can present in a similar manner to FAP. MUTYH is an important differential diagnosis in individuals with presumed de novo FAP, and genetic testing is the only means to differentiate between these two conditions, which have significantly different clinical implications to relatives of the affected individual. While the association of MUTYH gene mutations with hereditary CRC was first defined in patients with colorectal polyposis,67,68 subsequent population-based CRC studies have found that up to one third of patients with biallelic MUTYH mutations develop CRC without additional polyps being identified at the time of diagnosis.69,70 Hence MUTYH-associated CRC is not invariably associated with colorectal polyposis and is a diagnosis that should be considered in young onset CRC irrespective of polyp status. Patients with biallelic mutations in MUTYH have a 93-fold increased risk of CRC although this figure is subject to ascertainment bias.71 MAP is associated with duodenal polyposis (
