1、Familial risk-colorectal cancer:ESMO Clinical Practice GuidelinesJ. Balmaa1, F. Balaguer2, A. Cervantes3& D. Arnold4, on behalf of the ESMOGuidelines Working Group*1Department of Medical Oncology, Hospital Vall dHebron, Vall dHebron Institute of Oncology (VHIO), Universitat Autnoma de Barcelona, Bar
2、celona;2Department ofGastroenterology, Hospital Clnic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona;3Department of Hematology and Medical Oncology, INCLIVA, University ofValencia, Valencia, Spain;4Department of Medical Oncology, Tumor Biology Clinic, Albert Ludwigs University, Freiburg, Ger
3、many;These Clinical Practice Guidelines are endorsed by the Japanese Societyof Medical Oncology (JSMO)Lynch syndromeprevalence and penetrance of mismatch repairgene mutationsLynch syndrome is the most common hereditary colorectalcancer (CRC) syndrome and it accounts for 1%3% of allCRC burden 1. The
4、syndrome is transmitted with anautosomal-dominant pattern, and it is associated withmutations in the mismatch repair (MMR) genes, MLH1, MSH2,MSH6 and PMS2. These alterations lead to tumour DNAmicrosatellite instability (MSI) and foster inactivating mutationsin tumour suppressors containing microsate
5、llites in the codingregions (i.e. TGFBR2 and BAX) 2. Mutations in the MMRgenes may lead to a loss of expression of the correspondingprotein and be detected by immunohistochemistry techniques(IHCs) 3, 4.Overall, mutation carriers mainly have an increased risk ofCRC (lifetime risk 30%70%) and endometr
6、ial cancer(lifetime risk 30%60%) 1. Individuals with Lynchsyndrome also have an elevated risk of developing cancers ofthe urinary tract (8%), small intestine, ovary (4%12%),gastric, pancreas (4%), biliary tract, brain and skin 5. Agenotypephenotype correlation has been observed in whichMLH1 mutation
7、 carriers are at higher risk of young onsetCRC cancer, MSH2 at higher risk of extracolonic cancers,MSH6 at increased risk of endometrial cancer, and PMS2carriers show a lower absolute lifetime risk of CRC andendometrial cancer (15%20%) compared with othermutation carriers 6 (Figure 1).The term Turco
8、t syndrome refers to patients with MMR genemutations and brain tumours, and the term MuirTorresyndrome to patients with cutaneous gland tumours(keratoacanthomas, sebaceous adenomas or adenocarcinomas).referral for molecular screeningand mismatch repair gene testingSeveral clinical criteria were deve
9、loped for the clinicalsuspicion of Lynch syndrome, such as the Amsterdamcriteria and the revised Bethesda guidelines (Table 1)24, 7, 8. Nevertheless, several studies report that theAmsterdam criteria lack sensitivity and specificity foridentification of individuals with Lynch syndrome and somestudie
10、s have shown that the Bethesda guidelines may missbetween 6% and 25% of mutation carriers 3. Since 90% ofLynch syndrome CRC cases show MSI and/or loss of thecorresponding protein by IHC, upfront molecular screeningmight be a good strategy to identify candidates for germlinetesting. Recently, a poole
11、d-data analysis offour largepopulation-based cohorts of CRC probands has shown thatuniversal screening of CRC with tumour MMR testing wasmore sensitive than the Bethesda guidelines (100% versus87.8%) 9. On the other hand, the strategy of selectingpatients younger than 70 years, along with those olde
12、r than70 years fulfilling one of the Bethesda guidelines, missed only4.9% of Lynch syndrome cases, resulted in 34.8% fewer casesof MMR tumour testing, and 28.6% fewer cases undergoinggermline genetic testing than universal screening. Thisstrategy should be considered for clinical purposes, as thedia
13、gnostic yield was similar to universal screening (2.1%versus 2.2%) III, B.Regarding MMR tumour testing, MSI analysis is equivalentto IHC for case finding. The advantage of IHC is that it maydirect germline mutation analysis because loss of expression ofa protein is suggestive of an underlying geneti
14、c defect. If atumour with MMR deficiency is detected, germline genetictesting would be indicated. Nevertheless, in 10%15% ofsporadic CRC cases, MSI and loss of expression of MLH1 aredue to hypermethylation of the MLH1 gene promoter 10.Approved by the ESMO Guidelines Working Group: August 2006, last
15、update May2013. This publication supersedes the previously published versionAnn Oncol 2010;21 (Suppl. 5): v78v81.*Correspondence to: ESMO Guidelines Working Group,ESMO Head Office,Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;E-mail:clinicalguidelinesesmo.orgclinical practiceguidelinesclini
16、cal practice guidelinesAnnals of Oncology 24 (Supplement 6): vi73vi80, 2013doi:10.1093/annonc/mdt209Published online 27 June 2013 The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: . by gues
17、t on December 7, 2014http:/annonc.oxfordjournals.org/Downloaded from These sporadic cases are also frequently associated withthe somatic BRAF V600E mutation. Therefore, if lossof MLH1/PMS2 expression is observed, analysis of themethylation of the MLH1 promoter in the tumour oranalysis for somatic BR
18、AF V600E mutation should beperformed first III, B. On the other hand, analysis ofconstitutional MLH1 epimutations should be considered ina patient with suspected Lynch syndrome with loss ofMLH1/PMS2 expression if no germline mutation is identifiedin the MLH1gene III, B 11.Prediction models that esti
19、mate the likelihood offindinga MMR gene mutation constitute an effective clinical toolto identify individuals at risk of Lynch syndromewhich may help in clinical decision-making for referral andgermline genetic testing, especially in cases when notissue is available from any CRC patient in the famil
20、yIII, B 7, 12.mutation detectionApproximately 80% of mutations are located in the MLH1 andMSH2 genes, 10%12% in the MSH6 gene, and PMS2 mayaccount for 2%3% 1. Deletion of 30EPCAM leading tosubsequent somatic hypermethylation of MSH2 may accountfor up to 20% of the tumours with loss of expression of
21、MSH213. Pathogenic genetic alterations might be frameshift,nonsense or splice site mutations that lead to truncating orunstable proteins, but large deletions and rearrangements arealso common. Therefore, full germline genetic testing shouldinclude both DNA sequencing and large rearrangementanalysis
22、III, A.risk reduction: non-surgical preventiveoptionssurveillanceStudies have shown that the adenoma-carcinoma sequence isfaster in patients with Lynch syndrome. Colonoscopy at 3-yearintervals has demonstrated reduction in CRC incidence andCRC-related mortality III 14. However, cancers occurringduri
23、ng this interval have been detected in observational studies.We recommend initiating colonoscopy at age 2025 years andrepeating every 1 to 2 years III, C. No specific upper limit isestablished, and it should be based on the individuals healthstatus.Endometrial and ovarian cancer screening may be car
24、ried outon an annual basis from age 3035 years with gynaecologicalexamination, pelvic ultrasound, Ca125 analysis and aspirationbiopsy III, C.For gastric cancer, the search for the presence of HelicobacterPylori and subsequent eradication is recommended in mutationcarriers. In case of a high incidenc
25、e of gastric cancer in somepopulations, some experts recommend upper gastrointestinalendoscopy every 13 years.Surveillance for other Lynch-associated cancers is notrecommended due to the low sensitivity and specificity of thesurveillance techniques IV, C.chemopreventionRecent data from the Colorecta
26、l Adenoma/CarcinomaPrevention Program (CAPP2) have shown in a randomised,placebo-controlled trial a significant 60% reduction in theincidence of CRC and other Lynch syndrome-associatedcancers among those using 600 mg of aspirin per day for at least2 years 15. The rate of adverse events among patient
27、s takingFigure 1. Algorithm for molecular diagnosis of Lynch syndrome.Table 1. The Revised Bethesda Guidelines for testing colorectal tumoursfor microsatellite instability (MSI) 2Tumours from individuals should be tested for MSI in the followingsituations:1) Colorectal cancer diagnosed in a patient
28、who is 50 years of age.2) Presence of synchronous, metachronous colorectal or otherLynch-associated tumours,aregardless of age.3) Colorectal cancer with the MSI-H histologybdiagnosed in a patientwho is 60 years of age.c4) Colorectal cancer diagnosed in one or more first-degree relatives with aLynch-
29、related tumour, with one of the cancers being diagnosed underage 50 years.5) Colorectal cancer diagnosed in two or more first- or second-degreerelatives with Lynch-related tumours, regardless of age.aLynch syndrome-related tumours include colorectal, endometrial, stomach,ovarian, pancreas, ureter an
30、d renal pelvis, biliary tract and brain (usuallyglioblastoma as seen in Turcot syndrome) tumours, sebaceous glandadenomas and keratoacanthomas in MuirTorre syndrome, and carcinomaof the small bowel.bPresence of tumour infiltrating lymphocytes, Crohns-like lymphocyticreaction, mucinous/signet-ring di
31、fferentiation or medullary growth pattern.cThere was no consensus among the workshop participants on whether toinclude the age criteria in guideline 3 above; participants voted to keep 80% of mutationscorrespond to the G396D and Y179C missense variants(formerly annotated as G382D and Y165C, respecti
32、vely) 29.Initial studies showed that biallelic MUTYH mutationsaccounted for 10%20% of classical FAP cases without an APCmutation, and for 30% of AFAP cases 27. However, a recentstudy found biallelic MUTYH mutations in 2% (95% CI,0.2%6%) of patients with 1000 adenomas, 7% (95% CI, 6%8%) of patients w
33、ith 100999 adenomas, 7% (95% CI, 6%8%)of patients with 2099 adenomas and 4% (95% CI, 3%5%) ofpatients with 1019 adenomas 12. Due to the presence offounder mutations among ethnic groups, differences in thefrequency of MAP are likely to exist. The frequency of MUTYHheterozygotes in the general Europea
34、n population is 1%1.5%.Gene testing should commence with the investigation of anaffected individual. If the causative mutation is detected, thenpresymptomatic diagnosis can be offered to at-risk familymembers (i.e. siblings, because of the recessive nature of thedisease).screeningBecause of the simi
35、larity with AFAP, individuals shouldundergo total colonoscopy every 2 years, starting at the age of1820 years and continuing lifelong. Gene testing allows themost cost-effective screening to be carried out by drivingcolorectal examinations only to gene carriers. However, whenthe causative mutation i
36、s not identified, all at-risk familymembers should undergo colorectal screening III, B.Although less frequently than in FAP, patients with MAPmay develop extracolonic manifestations, i.e. duodenaladenomas. Accordingly, upper endoscopy starting at the age of2530 years is recommended, following the sa
37、me strategydescribed for APC-associated FAP III, B.CRC risk associated with monoallelic MUTYH carriers is stillunder debate. The magnitude of the association has beenrecently estimated, with a pooled odds ratio of 1.15 (95%CI=0.981.36) 30, 31. In such a context, it has been suggestedthat the Y179C m
38、utation confers a much stronger pathogenicitycompared with the G396D mutation. To date, CRC screening asrecommended for first-degree relatives of a patient withsporadic CRC is advised IV, C.treatmentColorectal management is similar to that proposed for patientswith AFAP. Because of the small number
39、of adenomas, in somepatients endoscopic polypectomy can be considered. However,when polyp burden exceeds the number that could be safelyTable 3. Summary of recommendations(i)Tumour testing with immunohistochemistry for MMR proteins and/or MSI should be considered in all CRC patients. As an alternate
40、 strategy, tumourtesting should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfil any of the Revised Bethesdaguidelines.(ii)If loss of MLH1/PMS2 is observed in the tumour, analysis of BRAF V600E mutation or analysis of the methylation of the MLH1 p
41、romoter should becarried out first to rule out a sporadic case.(iii)If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out.(iv)Full germline genetic testing should include DNA sequencing and large rearrangement analysis.(v)Follow-up recomm
42、endations in mutation carriers include colonoscopyevery 1 to 2 years, and gynaecological examination (with transvaginalultrasound, Ca125 and aspiration biopsy) on a yearly basis. Prophylactic gynaecological surgery might be an option in female carriers from age 35and after childbearing is completed.
43、(vi)Individuals with Familial CRC X syndrome are recommended colonoscopy at 35 year intervals, starting 510 years earlier than the youngest case inthe family.(vii)Patients with multiple colorectal adenomas (10) should be considered for germline genetic testing of APC and/or MUTYH.(viii)Full germline
44、 genetic testing of APC should include DNA sequencing and large rearrangement analysis.(ix)Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the Caucasian population, followed byanalysis of the entire gene in heterozygotes. Founder mutations amon
45、g ethnic groups should be taken into account.(x)In families with classic-FAP, sigmoidoscopy should be carried out every 2 years starting at the age of 1214 years and continued lifelong in mutationcarriers. Surgery is indicated if there are large numbers of adenomas, including adenomas showing a high
46、 degree of dysplasia.(xi)In families with attenuated-FAP, colonoscopy should be carried out every 2 years starting at the age of 1820 years and continued lifelong in mutationcarriers. Surgery is indicated if there are large numbers of adenomas, including adenomas showing a high degree of dysplasia.
47、Some patients withAFAP can be conservatively managed with annual colonoscopy and polypectomy.(xii)The decision on the type of colorectal surgery in FAP (total colectomy +IRAversus proctocolectomy +IPAA) depends on the age of the patient, theseverity of rectal polyposis, the wish to have children, th
48、e risk of developing desmoids and possibly the site of the mutation in the APC gene.(xiii)After colorectal surgery, surveillance of the rectum or pouch should be carried out.(xiv)In both classic and attenuated FAP, screening for extracolonic manifestations (gastroduodenal polyposis, thyroid cancer,
49、desmoid tumours) shouldstart when colorectal polyposis is diagnosed or at the age of 2530 years, whichever comes first.(xv)The suggested surveillance protocol for MAP patients is similar to that for patients with AFAP.clinical practice guidelinesAnnals of Oncologyvi | Balmaa et al.Volume 24 | Supple
50、ment 6 | October 2013 by guest on December 7, 2014http:/annonc.oxfordjournals.org/Downloaded from managed byendoscopy, total colectomy with IRA should beoffered. However, if rectal polyposis is severe, an IPAA is advised.Duodenal adenomas are usually managed as in AFAP III, B.surveillanceAfter total
