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Germline MUTYH gene mutations are not frequently found in unselected patients with papillary breast carcinoma
- Ewout P Boesaard†1,
- Ingrid P Vogelaar†1,
- Peter Bult2,
- Carla AP Wauters3,
- J Han JM van Krieken2,
- Marjolijn JL Ligtenberg1, 2,
- Rachel S van der Post2 and
- Nicoline Hoogerbrugge1Email author
© Boesaard et al.; licensee BioMed Central. 2014
Received: 1 May 2014
Accepted: 26 November 2014
Published: 12 December 2014
MUTYH- associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.
MUTYH- associated polyposis (MAP) is an autosomal recessive disease, which was first identified by El-Tassan et al. in 2002 . Several studies confirmed the association between germline MUTYH mutations and colorectal adenomas and colorectal carcinomas [2–4]. The MUTYH gene is involved in base excision repair (BER) preventing G:C → T:A conversions. These conversions are caused by oxidative damage forming 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxoG) resulting in a mis-incorporation of adenine that, if not repaired by MUTYH DNA glycosylase, could lead to a G:C → T:A conversion [5–7]. In the Dutch population the mutations p.Y179C, p.G396D and p.P405L account for approximately 90% of all MUTYH germline mutations [8, 9].
Several studies on extracolonic cancers in MAP patients have been performed. In one study in MAP patients in which the histological subtype of the breast tumors were included, two out of eleven breast cancers were described as intracystic papillary type . Also, the occurrence of MUTYH mutations in patients with breast cancer has been examined. Some of these studies found a significant increase in MUTYH mutations in breast cancer patients, while others could not find this potential association. [11–15]. Two of these studies specified the breast cancer histological subtypes of the patients. Out et al. found that minor allele genotypes of several MUTYH variants showed a trend towards association with lobular BC histology , while Rennert et al. found no differences for ductal or other BC histology type among 30 patients heterozygous for p.Gly396Asp or p.Tyr179Cys and 359 patients homozygous wild-type for these mutations .
Intracystic papillary breast cancer accounts for less than 1% of the total amount of breast cancer [16, 17], however, this type has been observed in an unexpectedly high proportion of MAP patients. We therefore wondered whether papillary carcinomas of the breast could be used as a hallmark to recognize patients with MAP. To explore whether biallelic MUTYH mutations are a frequent cause underlying the development of papillary carcinomas of the breast, we analyzed the prevalence of germline MUTYH mutations in an unselected patient group with papillary breast cancer.
The study group consisted of 74 patients with papillary carcinomas of the breast, including papillary ductal carcinoma in situ (DCIS), intraductal/intracystic papillary carcinomas and invasive papillary carcinomas, which were diagnosed between January 1990 and December 2012 in the Radboud university medical center, and between January 2002 and December 2012 in the Canisius Wilhelmina Hospital, Nijmegen. Cases were retrieved from the surgical pathology files. Information concerning other malignancies or polyposis coli was obtained from pathology records using the PALGA (nationwide histopathology and cytopathology data archive of the Netherlands) database. All records were anonymously listed in a database. Cases were treated according to the FEDERA (Dutch Federation of Biomedical Societies) code, with anonymous use of redundant tissue for research purposes.
Primers used for amplification
Forward primer (5' - 3')
Reverse primer (5' - 3')
p.G396D and p.P405L
Sequenced (N = 53)
All patients (N = 72)
52 female, 1 male
71 female, 1 male
Age at diagnosis (range)
67.5 years (range 22–89 years)
67.4 years (range 22–96 years)
– Papillary DCIS
– Intraductal/intracystic PC
– PC with invasive component
Patients with colon adenomas
Patients with colon carcinoma
N = 53
Our data do not confirm that biallelic germline MUTYH mutations are a frequent underlying cause of papillary carcinomas of the breast. Such relation was previously suggested by the results of Vogt et al. that showed an overrepresentation of intraductal papillary carcinomas of the breast in a MAP cohort . Papillary carcinomas of the breast are a group of tumors with a favorable prognosis . The terminology of papillary carcinomas has been widely disputed. The intraductal and intracystic papillary carcinomas were first considered as a form of carcinoma in situ, but it was shown that they often completely lack a myoepithelial layer and can be invasive . Some authors prefer to use the term encapsulated papillary carcinoma, which refers to intracystic and solid papillary tumors, which are circumscribed and mostly have a fibrous capsule . For this article, we have made a differentiation between papillary DCIS, intraductal or intracystic papillary carcinomas and papillary carcinomas with an invasive component. As the definition of the various histological variants of this malignant tumor differs in the literature, we decided to include in our study all the previously described papillary tumors. In our study, papillomas of the breast were excluded because a relation between this benign tumor and malignant papillary carcinomas has not been described.
In our study we could not identify the association between MUTYH mutations and papillary carcinomas of the breast in an unselected group of patients with papillary carcinomas. The current approach has been used in other studies in cancer predisposition syndromes. For example, patients with Familial Adenomatous Polyposis, caused by mutations in the APC gene, have a higher risk of developing desmoid tumors, but when a unselected cohort of this rare type of tumor is tested for APC mutations, only a small mutation detection rate has been found [22, 23]. The same accounts for patients with endometrial cancer that are screened for Lynch syndrome-predisposing genes [24, 25].
Based on the data presented in this study, an enrichment of biallelic MUTYH mutations in other patient cohorts cannot be excluded. This might be true for patients with other histological subtypes of BC, patients with very early onset of papillary carcinoma, patients with papillary carcinomas of the breast together with polyposis as well as patients with a family history of colon carcinomas. Our data, however, do indicate that papillary carcinomas of the breast cannot be used as a hallmark to recognize patients with MUTYH-associated polyposis.
The authors thank Manja Weijers, Department of Pathology, for excellent technical assistance.
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