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Other short opinions/comments on moderate/low cancer genetic risk markers in medical practice and the article Genetic contribution to all cancers: the first demonstration using the model of breast cancers from Poland stratified by age at diagnosis and tumour pathology by Lubinski et al., Breast Cancer Res Treat 2008 Apr 15
Kristiina Aittomki
Hereditary Cancer in Clinical Practice , 2008, DOI: 10.1186/1897-4287-6-2-67
Abstract: Allan SpigelmanProfessor University of New South Wales, Surgical Professorial Unit, St Vincent's Hospital Clinical School, NSW, AustraliaCorresponding author: Director Cancer Services St Vincent's and Mater Health Sydney, NSW, Australia, phone: +61283822354; +61283822328, e-mail: aspigelman@stvincents.com.auIt is an interesting pilot study that requires replication on a larger scale.Walter WeberBetriebs- und Forschungslaboratorium, Zweckverband Landeswasserversorgung, GermanyCorresponding author: Medical Oncology, Heuberg 16, CH-4051 Basel, e-mail: cancer@bluewin.chThis is an important step towards defining genetic risk factors of breast cancer. As a medical oncologist I expect that downstream functions of such common genetic variants will be potential targets for new drugs [1]. Old drugs could also become new drugs [2]. Pharmacoge-netics, the hereditary basis for inter-individual differences in drug effect, will predict patients at risk for extreme toxicity and altered efficacy of chemotherapy [3,4].Vladimir ZajacCancer Research Institute, Slovak Academy of Sciences, Laboratory of Cancer Genetics, Bratislava, Slovak RepublicCorresponding author: Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia, e-mail: vladimir.zajac@savba.skIt is practically impossible to find a paper in which the authors raise the basic issue - why there is such a high frequency of hereditary forms of cancer in the human population. I highly appreciate your approach and courage to go into this basic problem. I think that your hypothesis may bring a new impulse for the solution of this crucial question.I have a feeling that at the present time human genetics, after a very dramatic period of approximately 20 years, is entering a period of recession. The reason is that we are not able to answer the aforementioned question.Why do so many mutations in a very short part of human DNA result in various types of cancer diseases? This is mainly the case of the APC gene in the par
Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families
Hannaleena Eerola, P?ivi Heikkil?, Anitta Tamminen, Kristiina Aittomki, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2004, DOI: 10.1186/bcr953
Abstract: Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases.BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups.BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker.Women predisposed to hereditary or familial breast cancer form a heterogeneous group. It would be useful if we could identify carriers of the high-risk BRCA1 and BRCA2 genes and target the expensive and time-consuming genetic testing to individuals who most probably carry those mutations. Besides family history, histopathological markers could also be useful in distinguishing patients and families likely to carry a BRCA1/2 germline mutation from mutation-negative families and breast cancer patients in general.Several studies have compared the characteristics of breast cancers in BRCA1 carriers and in sporadic controls. Distinct features between BRCA1-associated tumours have been found, such as high tumour grade, oestrogen receptor (ER) negativity, and overexpression of p53 [1-3]. In addition, negativity for proges
Relationship of patients' age to histopathological features of breast tumours in BRCA1 and BRCA2 and mutation-negative breast cancer families
Hannaleena Eerola, P?ivi Heikkil?, Anitta Tamminen, Kristiina Aittomki, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2005, DOI: 10.1186/bcr1025
Abstract: Representative areas of all available breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2, and 74 non-BRCA1/2 breast cancer families were punched into a tissue microarray. Immunohistochemical staining of oestrogen receptor, progesterone receptor, ERBB2, and p53 as well as the histology and grade of tumours in these three groups of families were studied in different age groups and compared with each other.We found that only breast cancers from young (<50 years) BRCA1+ patients represent features documented as being typical of BRCA1-associated cancers, such as high tumour grade, negativity for oestrogen and progesterone receptors, and overexpression of p53. Among the BRCA2 families, the opposite was found, with a significantly higher frequency of tumours negative for oestrogen and progesterone receptors among the older patients than among the other groups, but no distinctive tumour characteristics among the younger BRCA2 patients.Tumours of BRCA1 and BRCA2 carriers aged 50 years or more differed significantly from those of younger carriers. This difference may reflect different biological behaviour and pathways of tumour development among the older and the younger BRCA1 and BRCA2 patients, with impact also on prognosis and survival.Distinct pathological features among BRCA1-associated tumours have been found when such tumours are compared with sporadic cancers; these features include high tumour grade, negativity for oestrogen receptor (ER), overexpression of p53, negativity for progesterone receptor (PR), and a higher proportion of medullary and atypical medullary carcinomas [1-3]. Recently, cDNA expression analyses have suggested a basal epithelial phenotype for BRCA1 tumors [4] and expression of cytokeratins 5/6 have been associated with BRCA1 tumours [5]. Among BRCA2-associated tumours, findings have been inconsistent, and in most cases no significant difference has been found between BRCA2-associated and sporadic cancers [1,2,6,7].In our previous rep
Comprehensive analysis of NuMA variation in breast cancer
Outi Kilpivaara, Matias Rantanen, Anitta Tamminen, Kristiina Aittomki, Carl Blomqvist, Heli Nevanlinna
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-71
Abstract: In order to evaluate the NuMa gene for breast cancer susceptibility, we have here screened the entire coding region and exon-intron boundaries of NuMa in 92 familial breast cancer patients and constructed haplotypes of the identified variants. Five missense variants were further screened in 341 breast cancer cases with a positive family history and 368 controls. We examined the frequency of Ala794Gly in an extensive series of familial (n = 910) and unselected (n = 884) breast cancer cases and controls (n = 906), with a high power to detect the suggested breast cancer risk. We also tested if the variant is associated with histopathologic features of breast tumors.Screening of NuMA resulted in identification of 11 exonic variants and 12 variants in introns or untranslated regions. Five missense variants that were further screened in breast cancer cases with a positive family history and controls, were each carried on a unique haplotype. None of the variants, or the haplotypes represented by them, was associated with breast cancer risk although due to low power in this analysis, very low risk alleles may go unrecognized. The NuMA Ala794Gly showed no difference in frequency in the unselected breast cancer case series or familial case series compared to control cases. Furthermore, Ala794Gly did not show any significant association with histopathologic characteristics of the tumors, though Ala794Gly was slightly more frequent among unselected cases with lymph node involvement.Our results do not support the role of NuMA variants as breast cancer susceptibility alleles.Recently, a genome-wide association study with over 25 000 single-nucleotide polymorphisms (SNP) was conducted to discover variants associated with increased breast cancer risk [1]. The initial sample set comprised of 254 German breast cancer cases and 268 controls [1]. Fifty-two SNPs were selected for replication genotyping in two independent sample series, one German (188 cases, 150 controls) and one Austra
Evaluation of SHOX copy number variations in patients with Müllerian aplasia
Maria Sandbacka, Mervi Halttunen, Varpu Jokimaa, Kristiina Aittomki, Hannele Laivuori
Orphanet Journal of Rare Diseases , 2011, DOI: 10.1186/1750-1172-6-53
Abstract: We used multiplex ligation-dependent probe amplification (MLPA) to study SHOX CNVs.All patients showed normal amplification of SHOX. Several aberrations, duplications and deletions, were found downstream of the gene in five patients and seven controls, but these were all copy number polymorphisms.Our study in an extensive cohort of patients with MA does not support a role for SHOX CNVs in the aetiology of the disorder. Further studies in the field are important for both patients looking for answers as well as for the scientific community for better understanding the regulation of the female reproductive duct development.The Müllerian ducts form the primordial basis for the female reproductive tract. They differentiate into the oviducts, uterus, and the upper two-thirds of the vagina during early embryonic development. A wide variety of malformations can occur if this development is disrupted. One such malformation is Müllerian aplasia (MA), also referred to as Mayer-Rokitansky-Küster-Hauser (MRKH, Online Mendelian Inheritance in Man [OMIM] #277000) syndrome or MURCS assosciation (Müllerian duct aplasia, Renal dysplasia and Cervical Somite anomalies, OMIM #601076) as renal and skeletal malformations are relatively common in patients with MA [1]. Women with MA are otherwise healthy with normal female chromosome constitution (46, XX) and normal secondary sexual characteristics. MA is commonly diagnosed in young adulthood due to primary amenorrhoea. The effects on sexual life with infertility often cause lifelong psychosocial problems making MA one of the most difficult disorders of female reproductive health. The minimum incidence of MA is 1 in 5000 newborn girls [2], and for the majority of the patients the cause is still unknown.During recent years, an increasing number of studies have aimed at investigating the genetic basis of MA. To date, only mutations in WNT4 (the wingless-type MMTV integration site family, member 4 gene) have been reported to cause MA [3-6]. Ho
Basal cytokeratins in breast tumours among BRCA1, BRCA2 and mutation-negative breast cancer families
Hannaleena Eerola, Mira Heinonen, P?ivi Heikkil?, Outi Kilpivaara, Anitta Tamminen, Kristiina Aittomki, Carl Blomqvist, Ari Ristim?ki, Heli Nevanlinna
Breast Cancer Research , 2008, DOI: 10.1186/bcr1863
Abstract: Using breast cancer tumour microarrays, immunohistochemical expression of cytokeratin (CK)-5/6, CK-14 and CK-17 was evaluated in breast tumours from BRCA1 families (n = 46), BRCA2 families (n = 40), non-BRCA1/BRCA2 families (n = 358) and familial breast cancer patients with one first-degree relative affected by breast or ovarian cancer (n = 270), as well as from patients with sporadic breast cancer (n = 364). Staining for CK-5/6, CK-14 and CK-17 was compared between these groups and correlated with other clinical and histological factors.CK-5/6, CK-14 and CK-17 were detected mostly among oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and high-grade tumours. We found the highest percentages of samples positive for these CKs among ER-negative/HER2-negative tumours. In univariate analysis, CK-14 was significantly associated with tumours from BRCA1 (39%; P < 0.0005), BRCA2 (27%; P = 0.011), and non-BRCA1/BRCA2 (21%; P < 0.005) families, as compared with sporadic tumours (10%). However, in multivariate analysis, CKs were not found to be independently associated with BRCA1 or BRCA2 mutation status, and the most effective predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status.Although our study confirms that basal CKs can help to identify BRCA1 mutation carriers, this effect was weaker than previously suggested and CKs did not independently predict BRCA1 mutation either from sporadic or familial breast cancer cases. The most effective, independent predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status, as compared with sporadic or non-BRCA1/BRCA2 cancers.Human breast cancers form a heterogeneous group of cancers. There are many subclassifications, and attempts have been made to identify differences between and characterize such subgroups. Earlier immunohistochemical studies, and recently gene expression studies as well, have been conducted to classify tumours [1]. One of the subgroup
MiR-34a Expression Has an Effect for Lower Risk of Metastasis and Associates with Expression Patterns Predicting Clinical Outcome in Breast Cancer
Hanna Peurala, Dario Greco, Tuomas Heikkinen, Sippy Kaur, Jirina Bartkova, Maral Jamshidi, Kristiina Aittomki, P?ivi Heikkil?, Jiri Bartek, Carl Blomqvist, Ralf Bützow, Heli Nevanlinna
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026122
Abstract: MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41–0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
Variants on the promoter region of PTEN affect breast cancer progression and patient survival
Tuomas Heikkinen, Dario Greco, Liisa M Pelttari, Johanna Tommiska, Pia Vahteristo, P?ivi Heikkil?, Carl Blomqvist, Kristiina Aittomki, Heli Nevanlinna
Breast Cancer Research , 2011, DOI: 10.1186/bcr3076
Abstract: We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.Hereditary predisposition to breast cancer is caused by variation in multiple genes affecting the cancer risk with varying penetrance. Mutations in the main high penetrance genes BRCA1 and BRCA2 are mostly found in families with multiple breast cancer cases particularly with early onset and with ovarian cancer [1,2], and may also affect breast cancer survival among the mutation carriers [3,4]. Strong familial breast cancer predisposition is also present in rare cancer s
Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications
Taru A Muranen, Dario Greco, Rainer Fagerholm, Outi Kilpivaara, Kati K?mpj?rvi, Kristiina Aittomki, Carl Blomqvist, P?ivi Heikkil?, ?ke Borg, Heli Nevanlinna
Breast Cancer Research , 2011, DOI: 10.1186/bcr3015
Abstract: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method.We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time.We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in
ATM variants and cancer risk in breast cancer patients from Southern Finland
Johanna Tommiska, Laila Jansen, Outi Kilpivaara, Hege Edvardsen, Vessela Kristensen, Anitta Tamminen, Kristiina Aittomki, Carl Blomqvist, Anne-Lise B?rresen-Dale, Heli Nevanlinna
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-209
Abstract: Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls.Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls.Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer.The ATM (Ataxia-Telangiectasia Mutated) kinase has an essential role in maintaining genomic integrity. It is a key activator of the cellular responses to DNA double-strand breaks [1]. Mutations in the ATM gene cause ataxia-telangiectasia (A-T) [2], a rare recessive disorder characterized by progressive neurodegeneration, cell cycle checkpoint defects, radiosensitivity and increased risk of cancer, particularly of lymphoid malignancies [3]. As radiation exposure is associated with an increased risk of breast cancer, the function of the ATM protein makes it a good candidate for a role in breast cancer predisposition [4]. The first suggestion that ATM might be a bre
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