Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 HEREDITARY COLON CANCER: LYNCH SYNDROME – PAST, PRESENT AND THE FUTURE HENRY T. LYNCH, MD JANE F. LYNCH, BSN Creighton University School of Medicine.

Similar presentations


Presentation on theme: "1 HEREDITARY COLON CANCER: LYNCH SYNDROME – PAST, PRESENT AND THE FUTURE HENRY T. LYNCH, MD JANE F. LYNCH, BSN Creighton University School of Medicine."— Presentation transcript:

1 1 HEREDITARY COLON CANCER: LYNCH SYNDROME – PAST, PRESENT AND THE FUTURE HENRY T. LYNCH, MD JANE F. LYNCH, BSN Creighton University School of Medicine Omaha, Nebraska

2 2 Problem Areas Dx of Lynch syndrome (LS) frequently missed. Classification of LS may be ambiguous. More than CRC (numerous extracolonic cancers). Multiple molecular/phenotypic heterogeneous concerns.

3 3 Family History  Must be comprehensive;  Cancer of all anatomic sites, verification whenever possible.

4 4 Why Pursue Cancer of All Anatomic Sites? Pertinent for any hereditary cancer syndrome Most identified by pattern of cancer expression, e.g.: breast and ovary (HBOC syndrome); CRC, endometrium, ovary, others (Lynch syndrome); sarcomas, breast, brain, multiple others in SBLA (Li- Fraumeni syndrome); medullary thyroid carcinoma and pheochromocytoma (MEN-2a and MEN-2b); melanoma and pancreatic cancer with CDKN2A (p16) mutation (FAMMM syndrome); diffuse gastric cancer and lobular breast cancer with CDH1 mutation (HDGC syndrome);...and the list goes on.

5 Genetic Counseling Mandatory Centers of Cancer Genetic Expertise Physician Role, unfortunately, often insufficient 5

6 6 Patient’s Modified Nuclear Pedigree

7

8

9 9 Colorectal Cancer Worldwide estimates for colorectal cancer during 2008*: Incidence – 1,233,711 Mortality – 608,644 Worldwide estimates for familial/hereditary CRC during 2008*: Lynch syndrome 3-5% of all CRC37,011-61,686 FAP <1% of all CRC<12,337 Familial 20% of all CRC246,742 *GLOBOCAN. The International Agency for Research on Cancer web site. URL: http://www.iarc.fr/

10 10 Familial/Hereditary CRC in US Annual CRC incidence in US: 142,570 Lynch syndrome3-5% of all CRC4,277 - 7,129 FAP<1% of all CRC<1,426 Familial 20% of all CRC28,514 Jemal et al. CA Cancer J Clin 60:277-300,2010.

11 11 Magnitude of the Problem Question: Why are these figures of such significant public health impact? Answer: Each hereditary cancer comes from a family that could benefit immensely from genetic counseling. DNA testing, surveillance, and highly-targeted management are the key! Problem: Significance of family frequently missed!

12 12 THE BEGINNING!

13 13 Archives of Internal Medicine Vol. 12, July-Dec., 1913

14 14 Archives of Internal Medicine Vol. 12, July-Dec., 1913

15 15 Arch Intern Med 117:206-212, 1966.

16 16 Arch Intern Med 117:206-212, 1966.

17 17

18 18

19 19

20 20 Arch Intern Med 141:607-611, 1981

21 21 Cancer Research 54:4590-4594, 1994.

22 22 Am J Gastroenterology 89:1978-1980, 1994.

23 23 How Aggressive? Of 225 CRC patients with LS, 10.2 % had CRC within 5 yr of colonoscopy. Other studies showed CRC within 3 yrs of colonoscopy. Conclusion: 1) Accelerated carcinogenesis; 2) Need shorter colonoscopy intervals. Am J Gastrology 89:1978-1980, 1994.

24 24 Cancer 83:259-266, 1998.

25 25 Survival continued Results: Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification); In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age; Cancer 83:259-266, 1998.

26 26 Survival continued Results: A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series. Cancer 83:259-266, 1998.

27 27 Am. J. Hum. Genet. 72:1088-1100, 2003

28 28 JAMA 291:718-724, 2004

29 29 Genetic Heterogeneity in HNPCC HNPCC is associated with germline mutations in any one of at least five genes Chr 2 Chr 3 Chr 7 MSH2 PMS1 MLH1 PMS2 MSH6

30 30 FUTURE!

31 31 Should we test all colorectal cancer for Lynch Syndrome? YES! Test everybody.

32 32 Search for LS Among CRC Affecteds* Evidence: Among 500 CRC patients, 18 (3.6%) had LS. Of these 18:  18 (100%) had MSI-H CRCs;  17 (94%) were correctly predicted by IHC;  only 8 (44%) were dx < 50 years;  only 13 (72%) met the revised Bethesda guidelines;  1/35 cases of CRC show LS. *Hampel et al. J Clin Oncol 26:5783-5788, 2008.

33 33 Molecular Genetic Screening for LS Recommendation*: All incident CRC and EC cases should be molecularly screened for LS. MSI highly sensitive (89.3%). IHC equally sensitive (91.2%), is inexpensive, is more readily available, and predicts the nonworking gene. IHC is preferred method to screen for LS*. *Hampel et al. J Clin Oncol 26:5783-5788, 2008.

34 34 Increased risk for certain extracolonic malignancies  Endometrial  Ovary  Stomach  Small bowel  Pancreas  Liver and biliary tree  Muir-Torre cutaneous features  Brain, (glioblastoma) – Turcot’s syndrome  Possible Prostate cancer and others  Breast cancer - controversial.

35 35 Cardinal Features of Lynch Syndrome Differentiating pathology features of LS CRCs: - more often poorly differentiated; - excess of mucoid and signet-cell features; - Crohn’s-like reaction; - medullary features; - significant excess of infiltrating lymphocytes within the tumor. Increased survival from CRC. Sine qua non for diagnosis is identification of germline mutation in MMR gene (most commonly MLH1, MSH2, MSH6) segregating in the family.

36 A B C D

37 37 Cancer 77:1836-1843, 1996.

38 38 Breast Cancer Research and Treatment 53:87-91, 1999.

39 39 Breast Cancer in the Danish HNPCC Register* 20 ♀ mutation carriers dx with BC at mean age of 50 years (33-66). Predominantly ductal carcinoma with extensive lymphocytic reactions in 8/14 evaluated tumors. MMR protein immunostaining showed loss of expression of MLH1, MSH2, or MSH6 corresponding to the mutations found in 7/16 investigated cases. *Jensen et al. Breast Cancer Res Treat 120:777- 782, 2010.

40 40 Dis Colon Rectum 53:77-82, 2010.

41 41 Times to subsequent CRC and subsequent abdominal surgery were significantly shorter in the control group (P <.006 and P <.04, respectively). No significant difference was identified with respect to survival time between the cases and controls. Conclusion: Even though no survival benefit was identified between the cases and controls the increased incidence of metachronous colorectal cancer and increased abdominal surgeries among controls warrant the recommendation of subtotal colectomy in patients with LS.

42 42 N Engl J Med 354: 261-269, 2006

43 43

44 44

45 BRAFV600E Mutations in MSI* The BRAFV600E mutation occurs exclusively in sporadic forms of MSI CRC. Combined analysis of MSI and BRAFV600E mutation is included in current protocols of LS since it is a reliable, fast, and low-cost strategy. Helps identify sporadic cases and avoids time- consuming and expensive screening of MMR germline mutation analysis. *Seruca et al. Expert Rev Gastroenterol Hepatol 3:5-9, 2009. 45

46 Algorithm 1.IHC on all colorectal patients on tumor block; 2.If positive, BRAF (if positive, then sporadic); 3.Only do full MMR genetic tests on patient IHC +. BRAF neg. 46

47 47 MORPHOLOGY SUSPICIOUS FOR MSI-H Run PCR test for MSI status Is there MSI-H? Run mutation analysis for BRAF V600E Is there BRAF V600E mutation? SPORADIC CRC WITH MSI-H NO EVIDENCE OF LYNCH SYNDROME Is there loss of staining with any of the Abs? IHC for MLH1, MSH2, MSH6, PMS2 PUTATIVE LYNCH SYNDROME MMR GENES MUTATION ANALYSIS Is there a mutation in MMR gene? LYNCH SYNDROME YES NO YES NO Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26 FAMILIAL CRC TYPE “X”

48 MSI Analysis A functional assay for the MMR proteins the MMR proteins

49 MSI Analysis

50

51

52 MSI High Data New – Focus on Mononcleotides

53 MSI and Therapeutic Implications Pharmacogenetics: 5-FU-based chemotherapy refractory in MSI CRCs; possible advantage of irinotecan-based therapy; the latter “not ready for prime time” but 5-FU approaching clinical acceptability. Boland and Goel. Gastroenterology 138:2073-2087, 2010. 53

54 MSI and Therapeutic Implications Virtually all studies show either no benefit or adverse effects in response to 5-FU-based adjuvant chemotherapy (reviewed by Boland and Goel.*) In vitro responses suggest that chemoresistance is seen for many chemotherapeutic agents.** *Gastroenterology 138:2073-2087, 2010. **Aebi et al. Cancer Res 56:3087-3090, 1996. 54

55 MSI and Therapeutic Implications* Currently, guidelines do not recommend using MSI status to determine whether or not to use chemotherapy. This recommendation merits a second look, given the wealth of data showing the inadequacy of 5- FU for CRC with MSI. Should be tested only in the context of a randomized clinical trial. *Boland & Goel. Gastroenterology 138:2073-2087, 2010. 55

56 56 Familial CRC Type “X” Amsterdam Criteria positive but lacking MSI and MMR mutations will constitute ~ 40% of those AC-I without MMR mutations and therein referred to as familial CRC type X.* 1) CRC > left side 2)  CRC and extra colonic CRC 3) Later age CRC onset 4) Molecular genetics (MSI and IHC or MMR mutation) ABSENT! *Lindor et al. JAMA 293:1979-1985, 2005.

57 57 Epithelial Cell Adhesion Molecule (EPCAM) Gene and Its Lynch Syndrome Connection* A portion of this ~40% lacking MMR mutations is caused by a mutation mechanism in the gene known as EPCAM. *Kovacs et al. Hum Mutat 30:197-203, 2009.

58 58 Polyadenylation Sequence 5’ EPCAM deletion Exons 8 and 9 and polyadenylation sequence Ligtenberg MJ, Nature Genetics 2009. Transcriptional read through Hypermethylation of the MSH2 promoter

59 59 Why LS with Site-Specific CRC? Deletion in EPCAM results in hypermethylation and incomplete silencing of MSH2. EPCAM mutation carriers may have phenotypic features that differ from carriers of MSH2 mutations – namely, an almost exclusive expression of site-specific CRC, thereby lacking extracolonic cancers.

60 60 c.859-1462_*1999del (4.9 kb, starting in intron 7 and including exons 8 & 9) EPCAM MSH2 American and Dutch families have the same deletion in the EPCAM gene Deletion Lightenberg, Nature Genetics 2009.

61 61 American and Dutch EPCAM mutations originate from a common ancestor Deletion and Region inherited from common ancestor Family R and the Dutch families share a 6.1 MB region surrounding the same EPCAM deletion indicating a common ancestor. Based on the size of the shared region it is estimated the deletion occurred 10 generations ago. Dutch Families Chromosome 2 Family R Chromosome 2

62 62 History of Family R* Ascertained by us in 1970 and followed continuously. 700 blood line relatives 327 individuals age ≥ 18, ≥ 25% pedigree risk Phenotype strikingly similar to LS but integral extracolonic cancers absent (site-specific CRCs) *Lynch et al. Cancer 56:934-938, 1985. Lynch et al. Cancer 56:939-951, 1985.

63 63 First patient identified with EPCAM mutation CRC affecteds EPCAM results

64 64 Family Information Service (FIS) Cost-effective and highly efficient way of educating and counseling all available family members from a geographic catchment area during a single setting. Makes best use of physician’s time and effort, has group therapy potential and patients welcome it.

65 65

66 66

67 67 Targeted CRC Screening Screening is melded to LS’s natural history: Proximal location  colonoscopy Early age of onset  beginning at age 25 Accelerated carcinogenesis  every 1-2 yrs < age 40, then annually Pattern of extra-colonic cancers  targeted screening

68 68 MSI/IHC in CRC* Conclusion: CRCs with MSI may show distinctive clinical, pathologic features: a) predominance of CRC in proximal colon; b) lymphocyte infiltration within tumor; c) poorly differentiated mucinous or signet cell appearance; d) better prognosis; e) differing response to chemotherapeutics; f) molecular screening all CRC cases. *Boland and Goel. Gastroenterology 138:2073-2087, 2010.

69 69

70 70 *Jensen et al. Breast Cancer Res Treat 120:777-782, 2010.

71 71 Breast Cancer in the Danish HNPCC Register* Defective MMR in a substantial proportion of the BCs studied links it to HNPCC. While the low number does not motivate surveillance, the observation supports a role for defective MMR in BC progression in LS. *Jensen et al. Breast Cancer Res Treat 120:777- 782, 2010.

72 MSI and Therapeutic Implications* Where did this knowledge originate? Through DNA MMR genes first identified in bacteria through exposure to cytotoxic mutagens (alkylating agents) and selecting for strains resistant to DNA damage. *Carethers et al. J Clin Invest 98:199-206, 1996. Ribic et al. N Engl J Med 349:247-257, 2003. 72

73 MSI and Therapeutic Implications* Resulting bacteria were hypermutable and resistant to DNA alkylation. Resistant to cytotoxic agents that acted by damaging DNA. Raised possibility that DNA MMR deficient cells might be relatively resistant to some types of cytotoxic chemotherapy. *Carethers et al. J Clin Invest 98:199-206, 1996. Ribic et al. N Engl J Med 349:247-257, 2003. 73

74 74 Cardinal Features of Lynch Syndrome AD – MMR mutations Proximal Earlier age of onset Accelerated carcinogenesis Extra colonic cancers Pathology – distinctive? ↑ survival


Download ppt "1 HEREDITARY COLON CANCER: LYNCH SYNDROME – PAST, PRESENT AND THE FUTURE HENRY T. LYNCH, MD JANE F. LYNCH, BSN Creighton University School of Medicine."

Similar presentations


Ads by Google