TINJAUAN PUSTAKA INTRODUCTION Colorectal cancer (CRC) is one of three most common cancer in Indonesia with incidence rate of 19.1 for men and 15.6 for women per 100.000 population 1 and also important cause of morbidity and mortality among non- infectious diseases in developing country. 2
Environmental factor is a dominant cause of CRC, however, inherited genetic factor is also signifcant in between 15% and 30% of cases, more than 5% of all CRC cases are associated with a highly penetrant dominant or recessive inherited syndrome. The most common form of colorecatal hereditary cancer syndrome is Lynch Syndrome accounted for 2% to 4% of all CRC cases. 3,4 Predisposed individual from Lynch syndrome family have approximately 60 to 80% life-time risk for developing CRC. 5 The most important step leading to the diagnosis of a hereditary cancer syndrome is collection of thorough family history of cancer, it is the most cost-efective method to identify hereditary cancer syndrome. 11 The focus should be on identifying cancer, the family members age at the frst diagnosis/onset of cancer, any pattern of multiple primary cancers, any association with phenotypic features that may be related to cancer, such as colonic adenomas; and documentation of pathological fndings whenever possible. These information will frequently help to identify a hereditary cancer syndrome in the family. 5 The risk associated with a family history of CRC depends on the number of afected relatives and the age at frst diagnosis. People with one family degree relatives (FDR) with CRC diagnosed at age >50 years have a relative risk (RR) of 2 to 3 for developing CRC, while subjects with two (or more) FDR with CRC diagnosed at any age, or with one FDR with CRC diagnosed before the age of 50 years have a relative risk of 4 to 6 for developing CRC. 6 After complete family history, molecular genetic testing may then provide verifcation of Lynch Syndrome diagnosis, whether a germ-line mutation is present in the family. 7 ETIOLOGY Lynch syndrome has been known historically as hereditary nonpolyposis colorectal cancer (HNPCC). It is characterized by an increased risk of colon cancer and other related cancer such as cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. 8 The life time risks for cancer in subject with Lynch syndrome are: 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years), 25%-60% for endometrial cancer in women (mean age at diagnosis 48-62 years), 6% to 13% for gastric cancer (mean age at diagnosis 56 years), and 4%-12% for ovarian cancer (mean age ABSTRACT Colorectal cancer (CRC) is one of three most common cancer in Indonesia. More than 5% CRC cases are associated with inherited gene mutation called Lynch Syndrome. Lynch syndrome is caused by a germline mutation in a mismatch repair gene (MMR) gene (MLH1, MSH2, MSH6, and PMS2). Individual with these gene mutation have approximately 60 to 80% life-time risk for developing CRC. Lynch syndrome is also related to increased risk of other cancers such as cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. Lynch syndrome is diagnosed based on family history according to criteria of National NCCN, immunohistochemistry and genetic testing. Identifcation of people who are predisposed to hereditary colorectal cancer is very important, to allow clinicians assess the efective prevention, early detection and intervention to decrease morbidity and mortality. Key words: Lynch syndrome, colorectal cancer, inherited gene mutation ABSTRAK Kanker kolorektal (KKR) merupakan satu dari tiga kanker terbanyak di Indonesia. Lebih dari 5% kasus KKR berkaitan dengan mutasi gen yang diturunkan yang disebut sebagai sindrom Lynch. Sindrom Lynch disebabkan oleh mutasi germline pada gen mismatch repair (MMR) yang meliputi MLH1, MSH2, MSH6, dan PMS2. Individu dengan mutasi gen tersebut memiliki 60-80% life-time risk untuk KKR. Sindrom Lynch juga berhubungan dengan peningkatan risiko kanker lain seperti kanker endometrium, ovarium, gaster, usus halus, traktus hepatobilier, traktus urinarius, otal dan kulit. Sindrom Lynch didiagnosis berdasarkan data riwayat keluarga sesuai kriteria NCCN, pemeriksaan imunohistokimia dan pemeriksaan genetika. Indentifkasi individu pengidap sindrom Lynch sangat penting untuk pencegahan, skrining, dan intervensi dini, dan untuk menurunkan angka mortalitas dan morbiditas. Catharina Endah Wulandari. Lynch Syndrome. Kata kunci: Sindrom Lynch, kanker kolorektal, mutasi gen yang diturunkan Alamat korespondensi email: catharinaawalliya@gmail.com Lynch Syndrome Catharina Endah Wulandari Pusat Riset Biomedis (Centre of Biomedical Research/CEBIOR), Fakultas Kedokteran Universitas Diponegoro, Semarang, Indonesia CDK-220/ vol. 41 no. 9 th. 2014 662 TINJAUAN PUSTAKA family with a germline mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or in EPCAM. Minimum criteria for clinical defnition of Lynch syndrome are listed below (Amsterdam I Criteria) 12 : At least three relatives with colorectal cancer (CRC); all of the following criteria should be present: 1. One should be a frst-degree relative of the other two 2. At least two successive generations must be afected 3. At least one of the relatives with colorectal cancer must have received the diagnosis before age of 50 years 4. Familial adenomatous polyposis (FAP) should be excluded 5. Tumors should be verifed by pathologic examination. Revised minimum criteria for clinical defnition of HNPCC (Amsterdam II Criteria) 9 : At least three relatives must have a cancer associated with hereditary nonpolyposis colorectal cancer (colorectal, cancer of endometrium, small bowel, ureter or renal pelvis); all of the following criteria should be present: 1. One must be a frst-degree relative of the other two 2. At least two successive generations must be afected 3. At least one of the relatives with cancer associated with hereditary non-polyposis colorectal cancer should be diagnosed before age of 50 years 4. Familial adenomatous polyposis (FAP) should be excluded in the colorectal cancer case(s) (if any) 5. Tumors should be verifed whenever possible. Revised Bethesda Guidelines for heredi- tary non-polyposis colorectal cancer/Lynch Syndrome and Microsatellite instability 1 : 1. Colorectal cancer diagnosed in a patient who is less than 50 years of age 2. Presence of synchronous or metachro- nous Lynch-syndrome associated tumor, regardless of age 3. Colorectal cancer with the MSI-H histo- logy diagnosed in a patient who is less than 60 years of age 4. Colorectal cancer diagnosed in patient with one or more frst-degree relatives with an LS-related cancer with one of the cancer being diagnosed under age 50 years 5. Colorectal cancer diagnosed in a patient with two or more frst- or second-degree relatives with LS-related cancer regardless of age. For this guideline, Lynch syndrome-related tumors included colorectal, endometrial, gastric, ovarian, pancreas, ureter, renal pelvis, biliary tract, small bowel carcinoma, brain and sebaceous skin tumors. Patients meeting the revised Amsterdam II and Bethesda Guidelines should be ofered to undergo tumor testing for microsatellite instability (MSI) and/or Immunohisto- chemistry (IHC) analysis of tumour. A high level of MSI (two or more microsatellite markers show tumour instability), or loss of expression of a DNA mismatch repair protein by IHC, comprise tumor phenotypes that indicate defective DNA mismatch repair. This fnding can be found in 90% colon cancers associated with Lynch syndrome, whereas in sporadic CRC it is found in about 15% of cases. 3 Diagnosis testing Revised Amsterdam II and Bethesda guide- lines are appropriate tools to help in selecting families for molecular genetic testing and/or IHC analysis of tumours to establish diagnosis of Lynch Syndrome. Patient meeting these criterias should be ofered to undergo these following tests: 1. Immunohistochemistry (IHC) Immunohistochemistry (IHC) detect the at diagnosis 42.5 years, approximately 30% are diagnosed before age 40 years). The risk for other Lynch syndrome-related cancers is lower, although the persentage is higher than in general population. 6,9 Lynch syndrome is caused by a germline mutation in a mismatch repair gene (MMR) gene (MLH1, MSH2, MSH6, and PMS2) and associated with tumors exhibiting microsatellite instability (MSI). Microsatellite is repetitive sequence of exist DNA. There is increase variability in the length of the sequences in tumors due to Lynch syndrome, called instability (Figure 1). 10 The four mismatch repair (MMR) genes are inherited by autosomal dominant pattern. These genes are normally responsible for correcting mistakes in genetic code, which is made of DNA. Because cells grow and divide, they make copies of their DNA and sometimes some minor mistakes occur. Normal cells have mechanisms to recognize and repair mistakes. But individuals who inherit one of the abnormal genes associated with Lynch syndrome lack the ability to repair these minor mistakes; accumulation of these mistakes leads to increasing genetic damage within cells and eventually can lead to becoming cancerous cells. 11 DIAGNOSIS According to the Guideline from National Comprehensive Cancer Network (NCCN), Lynch syndrome diagnosis can be establish- ed based on family history meeting Bethesda or Amsterdam criteria who have tumor microsatellite instability (MSI) or on the basis molecular genetic testing in an individual or Figure 1 Microsatellite instability Microsatellite Replication Adapted from Gruber SB, Kohlmann W. The genetics of hereditary nonpolyposis colorectal cancer. J Nat Comp Cancer Net. 2003;1:137-44. Normal Abnormal (Mismatch repair defect) 663 CDK-220/ vol. 41 no. 9, th. 2014 TINJAUAN PUSTAKA presence or absence of protein products expressed by mismatch repair genes. IHC for loss of MMR gene products (MLH1, MSH2, MSH6, PMS2) has 92% sensitivity for Lynch syndrome related to germline mutation, and can help pinpoint which gene to target for mutation analysis. a. A germline mutation in MLH1 results in loss of expression of protein MLH1/PMS2, b. A germline mutation in MSH2 result in loss of expression of protein MSH2/MSH6, however, c. A germline mutation in MSH6 and PMS2 typically do not result in loss of MSH2 or MLH1 expression due to the fact that these proteins are still present in other pairings. 2 IHC and related gene mutation are summarized in Table 1. Table 1 Expression of protein in IHC testing related to gene mutation Immunohistochemistry Mutation MLH1 MSH2 MSH6 PMS2 - + + - MLH1 + - - + MSH2 + + - + MSH6 + + + - PMS2 2. Microsatellite instability (MSI) testing of tumor tissue Genes in the mismatch repair (MMR) path- way play an important role for identifying and repairing single nucleotide mismatches and insertion or deletion loops that occur when cells grow and divide. Defects in the genes involved with mismatch repair cause an accumulation of somatic mutations in a cell, which may result in the cell developing malignant. Microsatellites are part of DNA with a repetitive sequence of nucleotides (e.g., AAAAA or CGCGCGCG) that are susceptible to errors when mismatch repair gene function is impaired. Cancers presenting in cells with defective mismatch repair gene function show an inconsistent number of micro- satellite nucleotide repeats when compared to normal tissue, this fnding called as microsatellite instability. 8 MSI, tested using panel of microsatellite markers, is compared in tumor tissue
and normal tissue. Five markers (BAT25, BAT26, D2S123, D5S346, and D17S250) are recommended by a 1997 NCI consensus. 3 A tumor is classifed as listed below: a. MSI-high if more than two (or >30%) of the markers show instability b. MSI-low if one (or <30%) of the markers show instability c. MSI-stable if 0 (or 0%) of the markers show instability 3. Mutation analysis Genes in the mismatch repair (MMR) path way (MLH1, MSH2, MSH6, PMS2) in which germ- line mutation could happen, cause Lynch syndrome. Currently, EPCAM gene has been found to be the cause of Lynch syndrome. Although EPCAM is not a MMR gene, Table 2 Summary of Germline Molecular Genetic Testing Used in Lynch Syndrome Gene Proportion of Lynch Syndrome attributed in this gene Test method Mutation detected MLH1 50% Sequence analysis Sequence variant Duplication/deletion analysis Exonic or whole-gene deletion MSH2 40% Sequence analysis Sequence variant Duplication/deletion analysis Exonic or whole-gene deletion MSH6 7-10% Sequence analysis Sequence variant Duplication/deletion analysis Exonic or whole-gene deletion PMS2 5% Sequence analysis Sequence variant Duplication/deletion analysis Exonic or whole-gene deletion EPCAM (TACSTD1) ~1-3% Duplication/deletion analysis Exonic or whole-gene deletion Abnormal expression or MSI-H/L Abnormal expression Normal expression Normal expression or MSS MSI-L/H MSI MSS IHC IHC or MSI Suspected Lynch Syndrome (Revised Bethesda Criterias) High probability of carrying a mutation Low probability of carrying a mutation Mutation analysis Possible phenocopy analysis second tumour Mutation analysis No mutation analysis Figure 2 Strategy for identifcation of patients with colorectal cancer with a mismatch repair gene defect 2 IHS, immunohistochemical; MSI, microsatellite instability; MSS, microsatellite stability CDK-220/ vol. 41 no. 9 th. 2014 664 TINJAUAN PUSTAKA recurrent germline deletions of the 3 region results in silencing the adjacent downstream MSH2 by hypermethylation. 4-5 This following chart summarize steps for Lynch syndrome diagnosis (Figure 2): MANAGEMENT In general, management of Lynch Syndrome can be divided into two goals; frst, management of colon cancer in a person with Lynch Syndrome, and the second, cancer risk management for related family in which Lynch syndrome diagnosis established (primary prevention). 1. Management of Colorectal Cancer The main treatment for colorectal cancer related to Lynch syndrome is surgical. Several studies have shown that Lynch syndrome patients have an increased risk of developing multiple (synchronous and metachronous) CRCs, therefore, if colon cancer detected, more extensive treatment (total or subtotal colectomy) with ileorectal anastomosis is recommended rather than a segmental or partial colonic resection. 4,8 In a study, a decision analysis was performed to compare the life expectancy for patients undergoing subtotal colectomy or partial colectomy for a primary CRC. The results showed that subtotal colectomy performed at a young age (47 years) would lead to an increased life expectancy of up to 2.3 years. 6 Though this result suggest that extensive surgical treat ment is efective in Lynch syndrome, it is important to consider the risk of developing a second cancer under appropriate (post- operative) surveillance and the efect of more extensive surgery on functional outcome and quality of life, to determine beneft to patient. 7 2. Cancer risk management a. Surveillance for Colorectal Cancer NCCN guideline recommend colonoscopy and removal of polyps (if positive) beginning at age 20-25 years or 10 years before the earliest age of CRC diagnosis in the family, and repeat every 1-2 years. 8 Several study showed that periodic examination by colonoscopy could detect CRC at an earlier stage, and reduce up to 63% risk of CRC and signifcantly reduce the mortality associated with CRC. 4,9 Periodic removal of polyps reduces the incidence of CRC in individuals with Lynch syndrome. 11 Prophylactic surgery is not routinely recommended for individuals at risk of CRC because colonoscopy is efective. Subtotal colectomy with ileorectal anastamosis has been advised by some experts if a colon cancer is detected because of the very high rate of metachronous CRC (up to 30%). 11 b. Surveillance for Extra-Colonic Cancer Extra-colonic cancer related to Lynch Syndrome includes endometrial cancer and ovarian cancer as the most common cancer, followed by gastric cancer and duodenal cancer, urinary tract cancer, pancreas, hepatobiliary tract and brain cancer with lower incidence. 8 Endometrial and ovarian cancer surveillance could include annual transvaginal ultrasound, pelvic examination, annual Pap smear, and/or endometrial biopsy and CA-125 blood test beginning at 25-30 years of age. 4,11,21 Upper gastrointestinal endoscopy could be used to screen for gastric and duodenal cancer. Annual screening urinalysis and cytology to detect cancer of renal pelvis is generally advised because inexpensive and noninvasive, although evidence of ef cacy is Continued screening Consider prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) if postmenopausal or family completed Endocopic polypectomy with follow-up colonoscopy every 1-2 y depending on: Location, character Surgical risk Patient preference Total abdominal colectomy with ileorectal anastomosis Consider TAH/BSO at time of colon surgery if postmenopausal or family completed Treatment for adenocarcinomas FOLLOW-UP Colon cancer: Colonoscopy at age 20-25 y or 10 y prior to the youngest age at diagnosis in the family, whichever comes first and repeat every 1-2 y. Extracolonic: Endometrial and ovarian cancer Consider referral to gynecologic oncologist for screening for gynecologic tumors Encourage patient education and prompt response to endometrial cancer symptoms Prophylactic hysterectomy and bilateral salpingoophorectomy is a risk reducing option for women who have completed childbearing. Gastric and duodenal cancer: consider upper GI endoscopy (including side-viewing examination) at age 25-30 y and repeat every 1-3 y depending on findings. Urothelial cancer: consider annual urinalysis CNS cancer: Annual physical examination; no additional screening recommendation have been made. Pancreatic cancer: No recommendation have been made. No pathologic finding Adenocarcinomas Adenoma Adenomas not amenable to endoscopic resection or high- grade dysplasia SURVEILLANCE Endoscopic rectal exam every 1-2 y Figure 3 Management of cancer risk in Lynch Syndrome 21 665 CDK-220/ vol. 41 no. 9, th. 2014 TINJAUAN PUSTAKA lacking. 11,21 No specifc screening for cancers of the pancreas, hepatobiliary tract, or brain is recommended. 21 Management for cancer risk are summarized by following chart (Figure 3): SUMMARY Colorectal cancer (CRC) is one of three most common cancer in Indonesia with incidence rate of 19.1 for men and 15.6 for women per 100.000 population 13 and also important cause of morbidity and mortality among non-infectious diseases in developing country. 14 The most common form of colorecatal hereditary cancer syndrome is Lynch Syndrome accounted for 2% to 4% of all CRC cases. 15,16 Revised Amsterdam II and Bethesda guidelines are appropriate tools to help in selecting families for molecular genetic testing and/or IHC analysis of tumours to establish diagnosis of Lynch Syndrome. Management of Lynch Syndrome can be divided to: frst, management of colon cancer in a person with Lynch Syndrome, and second, cancer risk management for related family (primary prevention). REFERENCES 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; in press 2. Oemiati R, Rahajeng E, Kristanto A. Prevalensi Tumor dan Beberapa Faktor yang Mempengaruhinya di Indonesia. Bul. Penelit. Kes. 2011; 39:190-204. 3. Kastrinos F, Syngal S. Screening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For? J. Clin. Oncol. 4. Vasen H, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer. J Med Genet 2007;44:353- 62. 5. Jong A, Vasen H. The frequency of a positive family history for colorectal cancer: a population-based study in the Netherlands. J Med 2006;64(10). 6. 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