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Breast Cancer Research
Published in: Breast Cancer Research 3/2012

Open Access 01-06-2012 | Research article

Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases

Authors: Johanna E Lotsari, Annette Gylling, Wael M Abdel-Rahman, Taina T Nieminen, Kristiina Aittomäki, Marjukka Friman, Reino Pitkänen, Markku Aarnio, Heikki J Järvinen, Jukka-Pekka Mecklin, Teijo Kuopio, Päivi Peltomäki

Published in: Breast Cancer Research | Issue 3/2012

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Abstract

Introduction

Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.

Methods

MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.

Results

The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.

Conclusions

Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.
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Literature
1.
2.
Vasen HF, Watson P, Mecklin JP, Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999, 116: 1453-1456. 10.1016/S0016-5085(99)70510-X.CrossRefPubMed
3.
Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993, 71: 677-685. 10.1002/1097-0142(19930201)71:3<677::AID-CNCR2820710305>3.0.CO;2-#.CrossRefPubMed
4.
Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006, 24: 2137-2150. 10.1200/JCO.2005.05.2308.CrossRefPubMed
5.
Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomaki P, Mecklin JP, Jarvinen HJ: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999, 81: 214-218. 10.1002/(SICI)1097-0215(19990412)81:2<214::AID-IJC8>3.0.CO;2-L.CrossRefPubMed
6.
Vasen HF, Morreau H, Nortier JW: Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer?. Am J Hum Genet. 2001, 68: 1533-1535. 10.1086/320610.CrossRefPubMedPubMedCentral
7.
Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Jarvinen HJ, Myrhoj T, Sunde L, Wijnen JT, Lynch HT: The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008, 123: 444-449. 10.1002/ijc.23508.CrossRefPubMedPubMedCentral
8.
Buerki N, Gautier L, Kovac M, Marra G, Buser M, Mueller H, Heinimann K: Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer. 2012, 51: 83-91. 10.1002/gcc.20935.CrossRefPubMed
9.
Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH, Dutch Lynch Syndrome Study Group, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins MA: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010, 102: 193-201. 10.1093/jnci/djp473.CrossRefPubMedPubMedCentral
10.
Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, du Sart D, Tucker K, Kirk J: Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2001, 68: 118-127. 10.1086/316942.CrossRefPubMed
11.
Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, Buchanan DD, Clendenning M, Giles GG, Winship I, Macrae FA, Goldblatt J, Southey MC, Arnold J, Thibodeau SN, Gunawardena SR, Bapat B, Baron JA, Casey G, Gallinger S, Marchand LL, Newcomb PA, Haile RW, Hopper JL, Jenkins MA: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012, 30: 958-964. 10.1200/JCO.2011.39.5590.CrossRefPubMedPubMedCentral
12.
Vasen HF, Mecklin JP, Khan PM, Lynch HT: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991, 34: 424-425. 10.1007/BF02053699.CrossRefPubMed
13.
da Silva FC, de Oliveira LP, Santos EM, Nakagawa WT, Aguiar Junior S, Valentin MD, Rossi BM, de Oliveira Ferreira F: Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry. Fam Cancer. 2010, 9: 563-570. 10.1007/s10689-010-9373-2.CrossRefPubMed
14.
Muller A, Edmonston TB, Corao DA, Rose DG, Palazzo JP, Becker H, Fry RD, Rueschoff J, Fishel R: Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res. 2002, 62: 1014-1019.PubMed
15.
Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J: Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer. 1996, 77: 1836-1843. 10.1002/(SICI)1097-0142(19960501)77:9<1836::AID-CNCR12>3.0.CO;2-0.CrossRefPubMed
16.
de Leeuw WJ, van Puijenbroek M, Tollenaar RA, Cornelisse CJ, Vasen HF, Morreau H: Correspondence re: A. Muller et al., Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res., 62: 1014-1019, 2002. Cancer Res. 2003, 63: 1148-1149.PubMed
17.
Shanley S, Fung C, Milliken J, Leary J, Barnetson R, Schnitzler M, Kirk J: Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer. 2009, 8: 251-255. 10.1007/s10689-008-9226-4.CrossRefPubMed
18.
Jensen UB, Sunde L, Timshel S, Halvarsson B, Nissen A, Bernstein I, Nilbert M: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat. 2010, 120: 777-782. 10.1007/s10549-009-0449-3.CrossRefPubMed
19.
Walsh MD, Buchanan DD, Cummings MC, Pearson SA, Arnold ST, Clendenning M, Walters R, McKeone DM, Spurdle AB, Hopper JL, Jenkins MA, Phillips KD, Suthers GK, George J, Goldblatt J, Muir A, Tucker K, Pelzer E, Gattas MR, Woodall S, Parry S, Macrae FA, Haile RW, Baron JA, Potter JD, Le Marchand L, Bapat B, Thibodeau SN, Lindor NM, McGuckin MA, Young JP: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res. 2010, 16: 2214-2224. 10.1158/1078-0432.CCR-09-3058.CrossRefPubMedPubMedCentral
20.
Adem C, Soderberg CL, Cunningham JM, Reynolds C, Sebo TJ, Thibodeau SN, Hartmann LC, Jenkins RB: Microsatellite instability in hereditary and sporadic breast cancers. Int J Cancer. 2003, 107: 580-582. 10.1002/ijc.11442.CrossRefPubMed
21.
Yee CJ, Roodi N, Verrier CS, Parl FF: Microsatellite instability and loss of heterozygosity in breast cancer. Cancer Res. 1994, 54: 1641-1644.PubMed
22.
Nystrom-Lahti M, Kristo P, Nicolaides NC, Chang SY, Aaltonen LA, Moisio AL, Jarvinen HJ, Mecklin JP, Kinzler KW, Vogelstein B: Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med. 1995, 1: 1203-1206. 10.1038/nm1195-1203.CrossRefPubMed
23.
Gylling A, Abdel-Rahman WM, Juhola M, Nuorva K, Hautala E, Jarvinen HJ, Mecklin JP, Aarnio M, Peltomaki P: Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study. Gut. 2007, 56: 926-933. 10.1136/gut.2006.114876.CrossRefPubMedPubMedCentral
24.
Gylling AH, Nieminen TT, Abdel-Rahman WM, Nuorva K, Juhola M, Joensuu EI, Jarvinen HJ, Mecklin JP, Aarnio M, Peltomaki PT: Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008, 29: 1351-1359. 10.1093/carcin/bgn133.CrossRefPubMed
25.
Joensuu EI, Abdel-Rahman WM, Ollikainen M, Ruosaari S, Knuutila S, Peltomaki P: Epigenetic signatures of familial cancer are characteristic of tumor type and family category. Cancer Res. 2008, 68: 4597-4605. 10.1158/0008-5472.CAN-07-6645.CrossRefPubMed
26.
Isola J, DeVries S, Chu L, Ghazvini S, Waldman F: Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol. 1994, 145: 1301-1308.PubMedPubMedCentral
27.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998, 58: 5248-5257.PubMed
28.
Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, Aittomaki K, Jarvinen HJ, Mecklin JP, Lindblom A, Peltomaki P: Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2003, 21: 3629-3637. 10.1200/JCO.2003.03.181.CrossRefPubMed
29.
30.
Nygren AO, Ameziane N, Duarte HM, Vijzelaar RN, Waisfisz Q, Hess CJ, Schouten JP, Errami A: Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res. 2005, 33: e128-10.1093/nar/gni127.CrossRefPubMedPubMedCentral
31.
Jeuken JW, Cornelissen SJ, Vriezen M, Dekkers MM, Errami A, Sijben A, Boots-Sprenger SH, Wesseling P: MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. Lab Invest. 2007, 87: 1055-1065. 10.1038/labinvest.3700664.CrossRefPubMed
32.
33.
Ikpatt OF, Kuopio T, Ndoma-Egba R, Collan Y: Breast cancer in Nigeria and Finland: epidemiological, clinical and histological comparison. Anticancer Res. 2002, 22: 3005-3012.PubMed
34.
Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer. 2005, 4: 219-225. 10.1007/s10689-004-3906-5.CrossRefPubMed
35.
Foulkes WD: Inherited susceptibility to common cancers. N Engl J Med. 2008, 359: 2143-2153. 10.1056/NEJMra0802968.CrossRefPubMed
36.
Lynch HT, Krush AJ: Cancer family "G" revisited: 1895-1970. Cancer. 1971, 27: 1505-1511. 10.1002/1097-0142(197106)27:6<1505::AID-CNCR2820270635>3.0.CO;2-L.CrossRefPubMed
37.
Park JG, Park YJ, Wijnen JT, Vasen HF: Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. Int J Cancer. 1999, 82: 516-519. 10.1002/(SICI)1097-0215(19990812)82:4<516::AID-IJC8>3.0.CO;2-U.CrossRefPubMed
38.
Chao EC, Lipkin SM: Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res. 2006, 34: 840-852. 10.1093/nar/gkj489.CrossRefPubMedPubMedCentral
39.
Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res. 2001, 61: 3225-3229.PubMed
40.
Geary J, Sasieni P, Houlston R, Izatt L, Eeles R, Payne SJ, Fisher S, Hodgson SV: Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer. 2008, 7: 163-172. 10.1007/s10689-007-9164-6.CrossRefPubMed
41.
Koninki K, Tanner M, Auvinen A, Isola J: HER-2 positive breast cancer: decreasing proportion but stable incidence in Finnish population from 1982 to 2005. Breast Cancer Res. 2009, 11: R37-10.1186/bcr2322.CrossRefPubMedPubMedCentral
42.
Wimmer K, Etzler J: Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?. Hum Genet. 2008, 124: 105-122. 10.1007/s00439-008-0542-4.CrossRefPubMed
43.
Cejka P, Stojic L, Mojas N, Russell AM, Heinimann K, Cannavo E, di Pietro M, Marra G, Jiricny J: Methylation-induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J. 2003, 22: 2245-2254. 10.1093/emboj/cdg216.CrossRefPubMedPubMedCentral
44.
Woerner SM, Benner A, Sutter C, Schiller M, Yuan YP, Keller G, Bork P, Doeberitz MK, Gebert JF: Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene. 2003, 22: 2226-2235. 10.1038/sj.onc.1206421.CrossRefPubMed
45.
Zhang S, Lloyd R, Bowden G, Glickman BW, de Boer JG: Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon. Oncogene. 2001, 20: 6066-6072. 10.1038/sj.onc.1204730.CrossRefPubMed
46.
Zlatanou A, Despras E, Braz-Petta T, Boubakour-Azzouz I, Pouvelle C, Stewart GS, Nakajima S, Yasui A, Ishchenko AA, Kannouche PL: The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol eta in response to oxidative DNA damage in human cells. Mol Cell. 2011, 43: 649-662. 10.1016/j.molcel.2011.06.023.CrossRefPubMed
47.
Verma M, Srivastava S: Epigenetics in cancer: implications for early detection and prevention. Lancet Oncol. 2002, 3: 755-763. 10.1016/S1470-2045(02)00932-4.CrossRefPubMed
48.
Buyru N, Altinisik J, Ozdemir F, Demokan S, Dalay N: Methylation profiles in breast cancer. Cancer Invest. 2009, 27: 307-312. 10.1080/07357900802350814.CrossRefPubMed
49.
Aktan-Collan K, Haukkala A, Mecklin JP, Uutela A, Kaariainen H: Psychological consequences of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC): a prospective follow-up study. Int J Cancer. 2001, 93: 608-611. 10.1002/ijc.1372.CrossRefPubMed
50.
Bryant H, Mai V: Impact of age-specific recommendation changes on organized breast screening programs. Prev Med. 2011, 53: 141-143. 10.1016/j.ypmed.2011.06.014.CrossRefPubMed
Metadata
Title
Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases
Authors
Johanna E Lotsari
Annette Gylling
Wael M Abdel-Rahman
Taina T Nieminen
Kristiina Aittomäki
Marjukka Friman
Reino Pitkänen
Markku Aarnio
Heikki J Järvinen
Jukka-Pekka Mecklin
Teijo Kuopio
Päivi Peltomäki
Publication date
01-06-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3205

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