Genetic predisposition for cancer : genes and genetic counseling

Breast cancer accounts for one third of all female cancer cases worldwide. A hereditary component accounts for 10-15% of all breast and ovarian cancer cases. The overall aim of this thesis is to evaluate and improve genetic diagnostic and genetic counseling in hereditary cancer patients.

A total of 215 counselees were enrolled to a questionnaire study which aimed to conceptualize risk perception and worry for cancer before and one week after initial oncogenetic counseling and one year after completed genetic investigations. The most incorrect risk perceptions were identified among unaffected counselees with low or the same risk than the general population. The unaffected counselees showed more accurate risk perceptions and decreasing worry for cancer after oncogenetic counseling. The affected counselees overestimated the risk of cancer for children and did not show any change in cancer worry. The relevance of preventive programs was well understood among counselees. (Paper I)

Germ-line mutations in BRCA1 and BRCA2 genes predispose to high risk for breast- and ovarian cancer. Penetrance of cancer among BRCA1/2 mutation carriers is incomplete suggesting that genetic- and environmental factors play a role as risk modifier. A large-scale genome-wide association study was performed to identify genetic modifiers of risk for developing breast and ovarian cancer in BRCA1 mutation carriers. The results revealed five SNPs on 19p13 associated with breast cancer risk. Two of these SNPs showed independent associations (rs8170, HR 1.26, 95% CI 1.17-1.35 and rs2363956 HR 0.84, 95% CI 0.80-0.89). The two SNPs showed similar association with estrogen receptor-negative tumors and with triple-negative tumors (Paper II)

A randomized questionnaire study was conducted as described above (Paper I). The aim was to evaluate the oncogenetic counseling process and to compare the impact of the initial part of the oncogenetic counseling, when conducted via telephone versus in-person. The results indicate that telephone pre-counseling works as well as in-person pre-counseling. The counselees showed high satisfaction rates with the oncogenetic counseling process. A considerable number of counselees experienced difficulties with the process of creating a pedigree and dissatisfaction with information on surveillance and prevention. The counselees were unsatisfied with the received emotional support during genetic counseling and information on recommended cancer prevention and surveillance. (Paper III)

To identify additional breast cancer predisposing genes, a genome-wide linkage study on fourteen large non-BRCA1/2 hereditary breast cancer families was performed. The linkage analyses identified five candidate loci with a HLOD above one. Regions indicating evidence of linkage are located on 6p21, 8q13, 11p12, 18q21 and 22q11. (Paper IV)

List of scientific papers

I. Rantala J, Platten U, Lindgren G, Nilsson B, Arver B, Lindblom A, Brandberg Y. Risk perception after genetic counseling in patients with increased risk of cancer. Hereditary Cancer in Clinical Practice. 2009, 23; 7(1):15.
https://doi.org/10.1186/1897-4287-7-15

II. Antoniou AC, Wang X, Fredericksen Z S, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D, EMBRACE, Peock S, Cook M, Oliver C, Frost D, Eccles D, Evans DG, Eeles R, Izatt L, Chu C, Douglas F, Paterson J, Stoppa-Lyonnet D, Houdayer C, Mazoyer S, Giraud S, Lasset C, Remenieras A, Caron O, Hardouin A, Berthet P, GEMO Study Collaborators, Hogervorst FBL, Rookus MA, Jager A, van den Ouweland A, Hoogerbrugge N, van der Luijt RB, Meijers-Heijboer H, Gómez García EB, HEBON, Devilee P, Vreeswijk MPG, Lubinski J, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Górski B, Cybulski C, Spurdle AB, Holland H, kConFab, Goldgar DE, John EM, Hopper JL, Southey M, Buys SS, Daly MB, Terry M-B, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Preisler-Adams S, Arnold N, Niederacher D, Sutter C, Domchek SM, Nathanson KL, Rebbeck T, Blum JL, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Blank SV,Friedman E, Kaufman B, Laitman Y, Milgrom R, Andrulis IL, Glendon G, Ozcelik H, Kirchhoff T, Vijai J, Gaudet MM, Altshuler D, Guiducci C, SWE-BRCA, Loman N, Harbst K, Rantala J, Ehrencrona H, Gerdes A-M, Thomassen M, Sunde L, Peterlongo P, Manoukian S, Bonanni B, Viel A, Radice P, Caldes T, de la Hoya M, Singer CF, Fink-Retter A, Greene MH, Mai PL, Loud JT, Guidugli L, Lindor NM, Hansen TVO, Nielsen FC, Blanco I, Lazaro C, Garber J, Ramus SJ, Gayther SA, Phelan C, Narod S, Szabo CI, MOD SQUAD, Benitez J, Osorio A, Nevanlinna H, Heikkinen T, Caligo MA, Beattie MS, Hamann U, Godwin AK, Montagna M, Casella C, Neuhausen SL, Karlan BY, Tung N, Toland AE, Weitzel J, Olopade O, Simard J, Soucy P, Rubinstein WS, Arason A, Rennert G, Martin NG, Montgomery GW, Chang-Claude J, Flesch-Janys D, Brauch H, GENICA, Severi G, Baglietto L, Cox A, Cross SS, Miron P, Gerty SM, Tapper W, Yannoukakos D, Fountzilas G, Fasching PA, Beckmann MW, dos Santos Silva I, Peto J, Lambrechts D, Paridaens R, Rüdiger T, Försti A, Winqvist R, Pylkäs K, Diasio RB, Lee AM, Eckel-Passow J, Vachon C, Blows F, Driver K, Dunning A, Pharoah PPD, Offit K, Pankratz VS, Hakonarson H, Chenevix-Trench G, Easton DF & Couch FJ. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population. Nature Genetics. 2010, 42:885-92.
https://doi.org/10.1038/ng.669

III. Platten U, Rantala J, Lindblom A, Brandberg Y, Lindgren G, Arver B. The use of telephone in genetic counseling versus in-person counseling: a randomized study on counselees' outcome. Familial Cancer. 2012, March 8.
https://pubmed.ncbi.nlm.nih.gov/22399327

IV. Rantala J, Picelli S, Marikkannu R, Aravidis C, Kontham V, Lindblom A. A genome-wide linkage search for breast cancer susceptibility genes. [Manuscript]