LYNCH SYNDROME: HEREDITARY CANCER, PAST AND PRESENT. HENRY T. LYNCH, MD Creighton University School of Medicine Omaha, Nebraska

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1 LYNCH SYNDROME: HEREDITARY CANCER, PAST AND PRESENT 1 HENRY T. LYNCH, MD Creighton University School of Medicine Omaha, Nebraska

2 Advancing Personalized/Precision Cancer Medicine* Why pursue molecular genetics?: 1. Genetic changes used to guide individual tx; 2 2. Sequencing technologies and DNA isolation methods; 3. Multiplex hotspot mutation testing at the point of care.** *Cescon & Bedard. J Clin Oncol 33: , **Wagle et al. Cancer Discov 2:82-93, 2012 Majewski et al. J Clin Oncol 33: , Pogue-Geile et al. J Clin Oncol 33: , 2015.

3 Advancing Personalized/Precision Cancer Medicine* 3 Clinical example: PIK3CA most commonly mutated oncogene in breast cancer, present in ~25% of HER2-positive tumors*; Majewski et al.** demonstrated that PIK3CA is actionable as a predictive biomarker for HER2- targeted therapies and could have major clinical consequences. *Cescon & Bedard. J Clin Oncol 33: , **J Clin Oncol 33: , 2015.

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5 Aldred Scott Warthin, M.D., Ph.D. ( ) A Renaissance Man -- physician, musician, teacher, writer, editor and, above all, a remarkably creative physician-scientist. Graduated from Cincinnati Conservatory of Music at age 21. Then became an assistant in internal medicine and published a paper entitled, Accentuation of the Pulmonary Second Sound: An Important Sign in the Diagnosis of Pericarditis, which was later named Warthin s Sign. 5

6 Aldred Scott Warthin, M.D., Ph.D. ( ) The history of LS begins in 1895 with Warthin s concern about cancer in his seamstress s family. He queried her and developed the pedigree. 6

7 Archives of Internal Medicine Vol. 12, July-Dec.,

8 Archives of Internal Medicine Vol. 12, July-Dec.,

9 History of Lynch Syndrome In 1962, Lynch identified a patient with a strikingly similar history. Depressed, alcoholic with DTs, all reportedly because of his fear of cancer. 9

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12 Science 260: ,

13 13 Molecular Classification of CRC Classification broadly divided into 2 general groups*: 1) genomic differences: chromosomal instability, accounting for 75-80% of all CRCs; 2) microsatellite instability (MSI) accounting for 15-20% of all CRCs. *Markowitz & Bertagnolli. N Engl J Med 361: , Al-Sohaily et al. J Gastroenterol Hepatol 27: , 2012.

14 Hereditary Cancer Syndromes: 14 Nuts and Bolts Family history; Hereditary cancer syndrome diagnosis; Genetic counseling; DNA studies; Highly targeted surveillance/management; Extend to all at-risk relatives; Physician education; Research problem of discrimination (insurance, employment); Strategies for wide-spread interest of familial cancer approach to cancer control, malpractice, molecular genetics, other.

15 Familial/Hereditary CRC in US 15 Annual CRC incidence in US: 142,820 Lynch syndrome 3-5% of all CRC 4,285-7,141 FAP <1% of all CRC <1,428 Familial 20% of all CRC 28,564 Siegel et al. CA Cancer 63:11-30,

16 16 Hereditary Cancer Syndromes Family History: Must be comprehensive; 3-4 generations with both maternal and paternal lineages (see modified nuclear pedigree); Cancer of all anatomic sites; Verification whenever possible.

17 Why Pursue Cancer of All Anatomic Sites? Pertinent for any hereditary cancer syndrome diagnosis; 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); multiple colonic polyps in FAP and several additional hereditary polyposis syndromes;...and the list goes on. 17

18 Patient s Modified Nuclear Pedigree 18

19 Lynch et al. Nat Rev Cancer 15: , 2015.

20 Family History (FH) 20 FH is the linchpin in this effort. Often ignored or insufficiently recorded compromising opportunity for targeting patients for DNA testing. Could enable more certainty for its targeted clinical translation, surveillance, and personalized medical management.* *Guttmacher et al. N Engl J Med 351: , 2004.

21 Could this be hereditary Colon Cancer 21

Polyposis Syndrome Ashkenazi I1307K CHEK2 (HBCC) MUTYH (MAP) TGFBR1 = as yet

22 22 Familial Hereditary AC-1 without MMR (Familial CRC of syndrome X ) Sporadic TACSTD1 (EPCAM) Constitutional mosaic epimutation (MLH1) FAP; AFAP Mixed Polyposis Syndrome Ashkenazi I1307K CHEK2 (HBCC) MUTYH (MAP) TGFBR1 = as yet undiscovered hereditary cancer variants PJS FJP CD BRRS Hamartomatous Polyposis Syndromes

23 Differential Diagnosis Lynch Syndrome Syndrome Gene CRC Risk Average age of dx Sporadic cancer 4.8% Lynch syndrome MLH1/MSH2 M: 27-74% F: 22-61% MSH6 M: 22-69% F: 10-30% M/F: 12% PMS2 M: 20% F: 15% FAP APC 100% Attenuated FAP APC 69% MUTYH-associated MUTYH % Juvenile polyposis SMAD4/BMPR1A 38-68% Peutz-Jeghers STK11 39% Cowden syndrome PTEN 9-16% Serrated polyposis Not known ~>50% 48 Syngal et al. Am J Gastroenterol 110: , 2015.

24 Cardinal Features of Lynch Syndrome 24 Family pedigree shows autosomal dominant inheritance pattern for syndrome cancers. Proximal (right-sided) CRC predilection: 70-85% of Lynch syndrome CRCs are proximal to the splenic flexure. Earlier average age of CRC onset than in the general population: - Lynch syndrome: 45 years; - general population: 63 years. Accelerated carcinogenesis, i.e., shorter time for a tiny adenoma to develop into a carcinoma: - Lynch syndrome: 2-3 years; - general population: 8-10 years. High risk of additional CRCs: 25-30% of patients who have surgery for a LS-associated CRC will have a second primary CRC within 10 years, if surgery was < a subtotal colectomy.

25 Increased risk for certain extracolonic malignancies Endometrial Ovary Stomach Small bowel Pancreas Liver and biliary tree Muir-Torre cutaneous features Brain, (glioblastoma) Torre syndrome features Prostate cancer Breast Adrenal cortical carcinoma and others. 25

26 Pathology of Lynch Syndrome 26 Differentiating pathology features of LS CRCs: - more often poorly differentiated; - excess of mucoid and signet-cell features; - Crohn s-like reaction; - 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.

27 Problem Areas 27 Dx of Hereditary Cancer frequently missed. Classification encumbered by phenotypic/genotypic heterogeneity. Labor Intensive: MD time limited; poor reimbursement. Paucity of patient/md interest and/or knowledge. Germline mutation, i.e., BRCA1/BRCA2, p53, MMR mutations (MLH, MSH2, MSH6, PMS2) very expensive.

28 28 Should we test all colorectal cancer for Lynch Syndrome? YES! Test everybody.

29 29 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: , 2008.

30 30 Evidence of Cost-Effectiveness in LS* Widespread CRC testing identifies LS; Yields substantial benefits at acceptable cost; Enables with an LS mutation to begin regular screening, have risk-reducing prophylactic gyn surg; Cost-effectiveness depends on participation rate among relatives at risk for LS. *Ladabaum et al. Ann Intern Med 155:69-79, 2011.

31 31 MSI Pathway Technical Aspects of Testing*: dmmr detected by immunohistochemistry (IHC) and MSI by polymerase chain reaction (PCR). Tumor classified as: MSI-high if 2 of 5 MSI markers show instability; MSI-low if only 1 of 5 markers is unstable; MSS if MSI markers show no expansion. *Zhang & Li. World J Gastrointest Oncol 5:12-19, Laghi et al. Oncogene 27: , 2008.

32 Mismatch Repair (MMR) Mutations Genetic Heterogeneity in Lynch Syndrome 32 MSH6 MSH2 MLH1 PMS2 PMS1 Chr 7 Chr 2 Chr 3 Lynch Syndrome is associated with germline mutations in any one of at least five genes

33 BRAF V600E mutation and LS 33 BRAF V600E mutation can sort this out since when detected it excludes LS and contributes to improved costeffectiveness of genetic testing for LS. *Clin Gastroenterol Hepatol 6: , 2008.

34 MORPHOLOGY SUSPICIOUS FOR MSI-H Run PCR test for MSI status Is there MSI-H? NO NO EVIDENCE OF LYNCH SYNDROME FAMILIAL CRC TYPE X YES NO Run mutation analysis for BRAF V600E Is there loss of staining with any of the Abs? YES PUTATIVE LYNCH SYNDROME Is there BRAF V600E mutation? NO IHC for MLH1, MSH2, MSH6, PMS2 MMR GENES MUTATION ANALYSIS YES SPORADIC CRC WITH MSI-H NO Is there a mutation in MMR gene? YES Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26 LYNCH SYNDROME 34

35 35 Patients with Deficient MMR Tumors Such patients have distinct clinicopathologic characteristics and have been associated with a better stage-adjusted prognosis as compared with those with proficient MMR tumors. Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair (MMR). Constitutes an important oncogenic molecular pathway in CRC. Present in ~15% of all CRC.

36 36 Patients with Deficient MMR Tumors MMR deficiency may predict tumor chemoresistance to 5FU adjuvant tx, especially in patients with somatic hypermethylation of MLH1 promotor but possibly not in those with germline MMR mutations. Preliminary data suggest that adding oxaliplatin to 5FU could restore benefit of adjuvant chemotherapy in MSI patients.

37 37 Survival Patients with dmmr/msi tumors are less likely to have lymph node and distant metastatic disease than patients with MMR-proficient (pmmr) tumors. The prevalence of the dmmr/msi phenotype decreases with advancing stage at dx from >20% in stage II to <4% in stage IV.

38 38 Survival (continued): In the aggregate, the hypothesis is that dmmr/msi tumors have reduced metastatic potential and that favorable biology compared with pmmr/mss tumors is supported.

39 Tumor infiltrating lymphocytes Cancer 91: , T. Smyrk, MD (Mayo, Rochester, MN)

40 40 Epigenetics and Lynch Syndrome* No pathogenic mutation identified in ~ one-third of LS. Now we have an alternative mechanisms of constitutional epimutation of 2 major MMR genes, MLH1 and MSH2. *Megan P. Hitchins, Ph.D., The Role of Epigenetics in Lynch Syndrome. Fam Cancer 12: , 2013

41 41 Epigenetics and Lynch Syndrome* Gene expression changes include methylation of cytosine bases within cytosine-guanine (CpG) dinucleotides, modifications of the histone core of nucleosomes and positioning of nucleosomes along the DNA sequence. We now have irrefutable evidence of the etiologic role of epimutations of MLH1 and MSH2 in LS. *Megan P. Hitchins, Ph.D., The Role of Epigenetics in Lynch Syndrome. Fam Cancer 12: , 2013

42 5 EPCAM deletion Exons 8 and 9 and polyadenylation sequence Polyadenylation Sequence Transcriptional read through Hypermethylation of the MSH2 promoter Ligtenberg MJ, Nature Genetics

43 43 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.

44 Endometrial (EC) and Ovarian Cancer Screening 44 Effectiveness of screening for EC and/or Ovarian cancer is unproven; Consequently, prophylactic surgery is the best option for who have completed their families.* *Manchanda et al. Curr Opin Obstet Gynecol 21:31-38, Schmeler et al. N Engl J Med 354: , 2006.

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48 Fallopian tube carcinomas may be common sites of primary carcinoma in Hereditary Breast Ovarian Cancer syndrome and the Lynch syndrome. 15/58 (26%) registered ovarian carcinomas in BRCA1 mutation carriers may have arisen in a fallopian tube. 1/7 (14%) registered ovarian carcinomas in BRCA2 mutation carriers may have arisen in a fallopian tube. 5/14 (38%) registered ovarian carcinomas in MLH1, MSH2 and MSH6 mutation carriers may have arisen in a fallopian tube. From Casey MJ et al., Presented at the NEAGO Annual Meeting, 2010 (Abstracts).

49 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 extracolonic cancers targeted screening 49

50 50 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.

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55 Genetic Disorders Predisposing to Pancreatic Cancer 55 FAMMM syndrome Hereditary pancreatitis Lynch Syndrome II Hereditary breast cancer (BRCA2) Ataxia Telangiectasia A single family with insulin dependent diabetes mellitus and nine cases of pancreatic cancer (concordance) through three generations Peutz-Jegher s syndrome

56 56 Genetic risk of pancreatic cancer Syndrome Mutated Gene PanCan Risk Reference Peutz-Jeghers STK11 (19p13) RR 132 (44-261) Gastroenterology 199 (2000) Hereditary Pancreatitis PRSS1 (7q35) SPINK1 (5q31) 50-fold Pancreatology 1:431 (2001) Cystic Fibrosis CFTR (7q35) 30-Fold NEJM 339 (1998) FAMMM p16 (9p21) Fold NEJM 333 (1995) FAP APC (5q13) RR 4.5 ( ) Gastroenterology 123 (2002) Hereditary Breast/Ovarian BRCA1 (17q21) BRCA2 (13q12) RR 2.26 ( ) RR 3.51 ( ) JNCI 94 (2002) JNCI 91 (1999) HNPCC MLH1 (3p21) MSH2 (2p16) Increased Cancer 78 (1996) AT ATM (11q23) Increased ClinGen 55(1999) von Hippel- Lindau VHL (3p25) Increased Cancer Research 62 (2002)

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GENETICS OF COLORECTAL CANCER: HEREDITARY ASPECTS By. Magnitude of the Problem. Magnitude of the Problem. Cardinal Features of Lynch Syndrome

GENETICS OF COLORECTAL CANCER: HEREDITARY ASPECTS By HENRY T. LYNCH, M.D. 1 Could this be hereditary Colon Cancer 4 Creighton University School of Medicine Omaha, Nebraska Magnitude of the Problem Annual