FaCD Online Syndrome Fact Sheet

Last updated: 23 May 2012

Name: Hereditary Breast-Ovarian Cancer, non-BRCA1/2

Synonym: BRCAX

Mode of Inheritance: AD

Genes

BARD1, mapped to 2q34-q35
BRCA3#, mapped to 13q21
CHEK2/CHK2, mapped to 22q12.1
RAD51C, mapped to 17q
RAD51D, mapped to 17q11
TP53, mapped to 17p13.1
XRCC2, mapped to 7q36.1

Tumor features

breast cancer
ovarian cancer (i.e. epithelial origin)

Tumor features (possible)

malignant mixed mullerian tumor of the ovary

Comment

Approximately 5-10 % of breast cancer and ovarian cancer patients in the general population are estimated to be carriers of a highly penetrant cancer susceptibility gene[1;2]. Presently it is unclear whether hereditary site-specific breast or site-specific ovarian cancer, i.e. disorders with a highly penetrant gene increasing exclusively breast cancer or ovarian cancer risk, exist [3]. Hereditary Breast-Ovarian Cancer is often clinically defined as the presence of at least 3 cases of breast and/or ovarian cancer in at least two successive generations, with one affected relative being a first degree relative of the other two (or a second degree relative in case of the apparent transmission of the gene through the paternal line).

BRCA1 is estimated to be mutated in approximately 45 % of hereditary breast cancer families and BRCA2 mutated in an similar percentage, although these percentages may be overestimated[4-6] and the contribution of genes other than BRCA1 and BRCA2 may be very significant[7;8]. Most of these genes have yet to be identified.

Homozygous RAD51C mutations cause a Fanconi anemia-like phenotype, whereas single highly penetrant germline mutations in the RAD51C gene have been observed in German families that had been diagnosed with breast cancer as well as ovarian cancer (6/480 pedigrees), but not in 620 breast cancer-only families[23]. Most of the breast cancers in the patients with RAD51C mutations were not receptor triple negative and the authors suggest that histopathological features are more like those of BRCA2-associated breast cancer rather than BRCA1 associated types[23]. A Finnish study has confirmed that the number of RAD51C mutations identified in familial breast cancer cases (1/147) and unselected ovarian cancer cases (1/232) is low[24]. RAD51D mutations increase the risk to develop ovarian cancer 6-fold, the risk for breast cancer is not significantly increased[25]. BARD1 mutations have been observed in some families[26,27]. XRCC2 mutations have been identified as a rare cause of familial breast cancer[28]. This study focussed on breast cancer cases, but one of the families with a mutation included a premenopausal ovarian cancer case[28].

The existence of a familial breast cancer susceptibility gene (BRCA3?) at 8p12-p22 has been suggested by some studies[9-11]. However, other studies[12] failed to find support for the hypothesis that this region harbours such a gene. In rare cases of breast-(ovarian) cancer families mutations in the TP53 gene are found[13-15]. Ford et al.[16] concluded that a large proportion, possibly the majority, of families with few cases of breast cancer and no male breast cancer or ovarian cancer are not due to either BRCA1 or BRCA2. The CHEK2 1100delC mutation has been identified as a low-penetrance breast cancer-susceptibililty allele, with a prevalance of 4,2% among families with non-BRCA1/2 breast cancer and a prevalance of 1.1% among healthy individuals[17].

In a Dutch cohort of BRCA1/2 mutation negative breast cancer families, linkage to 9q21-q22 was observed, however, no mutations were detected in this region[19]. Several other loci have been suggested to be involved[20].

The Breast Cancer Linkage Consortium reported on the pathology of non-BRCA1/2 familial breast cancers[18]. Compared with BRCA1/2 as well as sporadic cases, non-BRCA1/2 tumors were of lower histological grade. Histological subtypes between non-BRCA1/2 cases and BRCA2 cases or sporadic cases were not significant. However, they were more likely to be of an invasive lobular type than BRCA1 cases. A patient with an ovarian malignant mixed mullerian tumor, bilateral breast cancer and a family history of ovarian cancer and bilateral breast cancer, without a detectable BRCA1/2 mutation was reported as a possible example of BRCAX[21,22].

Links

Breast Cancer Linkage Consortium 18 1 08

References

[1] Lynch HT, Lynch JF. Breast cancer genetics in an oncology clinic: 328 consecutive patients. Cancer Genet Cytogenet 1986; 22:369-371.
[2] Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 77[11], 2318-2324. 1996.
[3] Liede A, Tonin PN, Sun CC, Serruya C, Daly MB, Narod SA, Foulkes WD. Is hereditary site-specific ovarian cancer a distinct genetic condition? Am J Med Genet 75[1], 55-58. 1998.
[4] Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod S, Lenoir GM, Lynch H, Feunteun J, Devilee P, Cornelisse CJ, Menko FH, Daly PA, Ormiston W, Mcmanus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994; 265:2088-2090.
[5] Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, Ghadirian P, Perret C, Moslehi R, Dion F, Faucher MC, Dole K, Karimi S, Foulkes W, Lounis H, Warner E, Goss P, Anderson D, Larsson C, Narod SA, Futreal PA. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 13[1], 120-122. 1996.
[6] Couch FJ, Deshano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, Ganguly A, Rebbeck T, Weber BL. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 1997; 336(20):1409-1415.
[7] Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, Goldgar D, Narod SA, Lynch HT, Lenoir GM. Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes? Am J Hum Genet 60[3], 486-495. 1997.
[8] Schubert EK, Lee MK, Mefford HC, Argonza RH, Morrow JE, Hull J, Dann JL, King MC. BRCA2 in American families with four or more cases of breast or ovarian cancer: Recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet 60[5], 1031-1040. 1997.
[9] Sobol H, Birnbaum D, Eisinger F. Evidence for a third breast cancer susceptibility gene. Lancet 1994; 344:1151-1152.
[10] Kerangueven F, Essioux L, Dib A, Noguchi T, Allione F, Geneix J, Longy M, Lidereau R, Eisinger F, Pebusque MJ, Jacquemier J, Bonaitipellie C, Sobol H, Birnbaum D. Loss of heterozygosity and linkage analysis in breast carcinoma: Indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene 1995; 10:1023-1026.
[11] Seitz S, Rohde K, Bender E, Nothnagel A, Kolble K, Schlag PM, Scherneck S. Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: Linkage analysis in German breast cancer families. Oncogene 14[6], 741-743. 1997.
[12] Rahman N, Teare MD, Seal S, Renard H, Mangion J, Cour C, Thompson D, Shugart Y, Eccles D, Devilee P, Meijers H, Nathanson KL, Neuhausen SL, Weber B, Chang-Claude J, Easton DF, Goldgar D, Stratton MR. Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22. Oncogene 2000; 19(36):4170-4173.
[13] Buller RE, Anderson B, Connor JP, Robinson R. Familial ovarian cancer. Gynecol Oncol 1993; 51:160-166.
[14] Jolly KW, Malkin D, Douglass EC, Brown TF, Sinclair AE, Look AT. Splice-site mutataion of the p53 gene in a family with hereditary breast-ovarian cancer. Oncogene 1994; 9:97-102.
[15] Sidransky D, Tokino T, Helzlsouer K, Zehnbauer B, Rausch G, Shelton B, Prestigiacomo L, Vogelstein B, Davidson N. Inherited p53 gene mutations in breast cancer. Cancer Res 1992; 52:2984-2986.
[16] Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H, Seitz S, Cannon-Albright LA, Schofield A, Zelada-Hedman M. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62[3], 676-689. 1998.
[17] Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002; 31(1):55-59.
[18] Lakhani SR, Gusterson BA, Jacquemier J, Sloane JP, Anderson TJ, van de Vijver MJ, Venter D, Freeman A, Antoniou A, McGuffog L, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, Mcmanus R, Scherneck S, Ponder BAJ, Futreal PA, Peto J, Stoppa-Lyonnet D, Bignon YJ, Struewing JP, Bishop DT, Klijn JGM, Devilee P, Cornelisse CJ, Lasset C, Lenoir G, Barkardottir RB, Egilsson V, Hamann U, Chang-Claude J, Sobol H, Weber B, Easton DF, Stratton MR. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 2000; 6(3):782-789.
[19] Oldenburg RA, Kroeze-Jansema KH, Houwing-Duistermaat JJ, Bayley JP, Dambrot C, van Asperen CJ, van den Ouweland AM, Bakker B, van Beers EH, Nederlof PM, Vasen H, Hoogerbrugge N, Cornelisse CJ, Meijers-Heijboer H, Devilee P. Genome-wide linkage scan in Dutch hereditary non-BRCA1/2 breast cancer families identifies 9q21-22 as a putative breast cancer susceptibility locus. Genes, chromosomes & cancer 2008; epub ahead of publication.
[20] Bergman A, Karlsson P, Berggren J, Martinsson T, Björck K, Nilsson S, Wahlström J, Wallgren A, Nordling M. Genome-wide linkage scan for breast cancer susceptibility loci in Swedish hereditary non-BRCA1/2 families: suggestive linkage to 10q23.32-q25.3. Genes, chromosomes & cancer 2007; 46(3):302-9.
[21] Burns BA, Geisler JP, Hatterman-Zogg MA, De Young B, Buller RE. Malignant mixed mullerian tumor of the ovary and bilateral breast cancer: an argument for BRCA3, or a coincidental cluster of unconnected cancers?. Gynecologic oncology 2003; 91(2):426-8.
[22] Swisher E. Comment on "Malignant mixed Mullerian tumor of the ovary: an argument for BRCA3 or a coincidental cluster of unconnected cancer". Gynecologic oncology 2004; 95(3):773-4; author reply 774.
[23] Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010 May;42(5):410-4.
[24] Vuorela M, Pylkäs K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt Wäppling A, Haanpää M, Puistola U, Rosengren A, Anttila M, Kosma VM, Mannermaa A, Winqvist R. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat. 2011 Jul 13. [Epub ahead of print]
[25] Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L; Breast Cancer Susceptibility Collaboration (UK), Eccles D, Evans DG, Renwick A, Seal S, Lord CJ, Ashworth A, Reis-Filho JS, Antoniou AC, Rahman N. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011 Aug 7. [Epub ahead of print].
[26] Ratajska M et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast cancer research and treatment 2012; 131:89-97.
[27] Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proceedings of the National Academy of Sciences of the United States of America 2011; 108:18032-7.
[28] Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A; Breast Cancer Family Registry; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 2012 Apr 6;90(4):734-9.