Are <Emphasis Type="Italic">BRCA1</Emphasis>- and <Emphasis Type="Italic">BRCA2</Emphasis>-related breast cancers associated with increased mortality?

There has been contradictory evidence as to whether BRCA1 associated breast cancers have a poorer prognosis than non-BRCA1 cancers. In this issue of Breast Cancer Research Robson and colleagues provide further evidence for poorer survival in BRCA1 carriers and show that it could be attributed to failure to treat small node-negative grade 3 breast cancers with chemotherapy. There still remains little evidence for a survival difference for BRCA2 related breast cancers. Although the high contralateral breast cancer risk is confirmed by this study there is no real evidence for an increase in ipsilateral recurrence or new primary breast cancers in mutation carriers up to the 10-year point.     

<Emphasis Type="Italic">Estrogen receptor</Emphasis> α, <Emphasis Type="Italic">BRCA1</Emphasis>, and <Emphasis Type="Italic">FANCF</Emphasis> promoter methylation occur in distinct subsets of sporadic breast cancers

Introduction Alcohol intake has been consistently associated with breast cancer risk, but the importance of timing of intake and the impact of beverage type are unclear. Methods We evaluated whether early, lifetime or recent alcohol intake was associated with breast cancer risk, and whether risk varied by type of alcoholic drinks in 1,728 newly diagnosed population-based breast cancer patients and 435 control subjects aged 20–49 years. We used multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) as measures of the relative risk of breast cancer associated with intake of alcoholic drinks. Results Intake of alcoholic drinks during the recent five year period before the breast cancer diagnosis was associated with increased breast cancer risk (P _trend = 0.04). Intake of two or more alcoholic drinks per day during this five year period was associated with an 82% increase in breast cancer risk relative to never drinkers (OR = 1.82, 95% CI = 1.01–3.28). No risk increase was observed for alcohol intake at ages 15–20 years or for lifetime alcohol intake. Risk did not vary by type of alcohol consumed. Conclusions Our results suggest that recent alcohol consumption may be associated with increased breast cancer risk in young women.     

Prevalence of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in unselected breast cancer patients from Medellín,Colombia

Background

Approximately 5% of all breast cancers can be attributed to a mutation in the BRCA1 or BRCA2 gene. The genetic component of breast cancer in Colombia has been, for the most part, studied on cases from the Bogota region. Five different founder mutations have been identified in two studies of breast cancer patients in the Bogota region. It is important that the frequency of mutations be established among unselected cases of breast cancer of other regions of Colombia in order to estimate the genetic burden of this cancer in Colombia and to plan genetic services. The aim of this study was to establish the mutation frequencies of the BRCA genes in breast cancer patients unselected for family history or age, from Medellin, Colombia.

Methods

We enrolled 280 unselected women with breast cancer from a large public hospital in Medellin, Colombia. A detailed family history from each patient and a blood sample was obtained and processed for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques including a panel of recurrent Hispanic BRCA mutations which consists of fifty BRCA1 mutations and forty-six BRCA2 mutations, including the five recurrent Colombian BRCA mutations. All mutations were confirmed by direct sequencing.

Results

Genetic testing was successfully completed for 244 of the 280 cases (87%). Among the 244 cases, three deleterious mutations were identified (two in BRCA1 and one in BRCA2), representing 1.2% of the total. The average age of breast cancer in the mutation-positive cases was 34 years. The two BRCA1 mutations were known founder mutations (3450del4 in exon 11 and A1708E in exon 18). The BRCA2 mutation was in exon 11 (5844del5) and has not been previously reported in individuals of Colombian descent. Among the three mutation-positive families was a breast cancer family and two families with no history of breast or ovarian cancer.

Conclusion

The frequency of BRCA mutations in unselected breast cancer cases from the Medellin region of Colombia is low and is approximately 1.2%.

     

Relative contributions of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations to “triple-negative” breast cancer in Ashkenazi Women

Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry a founder mutation in BRCA1 or BRCA2. There is an association between BRCA1 mutations and “triple-negative” breast cancer (TNBC) [estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative]. We sought to determine the predictive value of the TNBC phenotype for the presence of a BRCA mutation in AJ women ascertained without respect to family history. DNA samples were collected between 8/2000 and 6/2004 from a prevalent cohort of unselected AJ women with breast cancer (median age at diagnosis 56 years). Samples (n = 451) were genotyped for AJ founder mutations. 352 (78.0%) cancers were ER positive, 254 (56.3%) PR positive, and 91 (20.2%) ER negative/PR negative. 63 (14.0%) cancers were HER2 positive (immunohistochemistry 3+ or FISH >2.2). TNBC was observed in 64 patients (14.2%). Founder mutations were detected in 48 samples (10.6%) including 25/64 TNBC (39.1%; 19 BRCA1, 6 BRCA2). Among TNBC patients with family history (FH) information, 6/15 (40%) mutations were found in women without breast or ovarian cancer in a close relative. The positive predictive value of TNBC for a BRCA1 mutation was 30% overall, 50% in women diagnosed<50 years, and 14% in women diagnosed ≥50. TNBC was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TNBC. The prevalence of BRCA founder mutations exceeds 50% in subsets of AJ women with TNBC. FH is an imperfect predictor of mutation status in this group. A significant number of mutation-associated TNBC are due to BRCA2.     

Phenocopy breast cancer rates in Israeli <Emphasis Type="Italic">BRCA1</Emphasis><Emphasis Type="Italic">BRCA2</Emphasis> mutation carrier families: is the risk increased in non-carriers?

BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7–92.8 years). Of these true negatives, 20 women (6.51–2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 –60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.     

Smoking and risk of breast cancer in carriers of mutations in <Emphasis Type="Italic">BRCA1</Emphasis> or <Emphasis Type="Italic">BRCA2</Emphasis> aged less than 50 years

Background Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2. Methods We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site. Results Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6–3.5) for BRCA1 carriers and 2.6 (1.8–3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p < 0.001) in both groups. Conclusions These results indicate that smoking is associated with increased risk of breast cancer before age 50 years in BRCA1 and BRCA2 mutation carriers. If confirmed, they provide a practical way for carriers to reduce their risks. Previous studies in prevalent mutation carriers have not shown smoking to increase risk of breast cancer, but are subject to bias, because smoking decreases survival after breast cancer. Northern California Family Registry for Breast Cancer: AS Whittemore, Stanford University School of Medicine, EM John, Northern California Cancer Center, A Felberg, Stanford University School of Medicine, V McGuire, Stanford University School of Medicine, DW West, Northern California Cancer Center, A Miron, Dana-Farber Cancer Institute, Harvard Medical School, DC Thomas, USC Keck School of Medicine, R Haile, USC Keck School of Medicine and Norris Comprehensive Cancer. Fox Chase Familial Breast Cancer Registry: M Daly, Fox Chase Cancer Center, A Godwin, Fox Chase Cancer Center, E Ross, Fox Chase Cancer Center. Coriell Institute: J Beck. New York Familial Breast Cancer Registry: MB Terry, Joseph L. Mailman School of Public Health, Columbia University. Utah Breast Cancer Family Registry: SS Buys, Huntsman Cancer Institute, V Venne, Huntsman Cancer Institute. Australian Breast Cancer Family Study: JL Hopper, The University of Melbourne, GG Giles, The Cancer Council Victoria, MRE McCredie, University of Otago, New Zealand, RL Milne, Spanish National Cancer Centre, MC Southey, The University of Melbourne, MA Jenkins, The University of Melbourne, C Apicella, The University of Melbourne. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre. Ontario Familial Breast Cancer Registry: I Andrulis, Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, NF Boyd, Ontario Cancer Institute, J Knight, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, H Ozcelik, Samuel Lunenfeld Research Institute, Mount Sinai Hospital. Correspondence to: Dr NF Boyd, Campbell Family Institute for Breast Cancer Research, Room 10-415, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario, Canada M5G 2M9. Boyd@uhnres.utoronto.ca     

Association of genetic polymorphisms of <Emphasis Type="Italic">ER-α</Emphasis> and the estradiol-synthesizing enzyme genes <Emphasis Type="Italic">CYP17</Emphasis> and <Emphasis Type="Italic">CYP19</Emphasis> with breast cancer risk in Chinese women

Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-α and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western countries. Therefore, we hypothesized that SNPs in ER-α and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms in the regulatory regions of ER-α (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk associated with these polymorphisms. We found that the T allele frequency of ER-α was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11–2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13–2.65) and premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03–3.09), particularly for ER +/PR + tumors. Furthermore, there were joint effects between CYP19 T and ER-α T varint genotypes (aOR = 1.67, 95% CI = 1.03–2.69 for CYP19 TC + TT vs. CC among ER-α T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11–2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-α rs3798577 are associated with breast cancer risk among Chinese women.     

Genetic polymorphisms of <Emphasis Type="Italic">TGF-β</Emphasis>1 &; <Emphasis Type="Italic">TNF-β</Emphasis> and breast cancer risk

Objective. The proliferation of malignant breast epithelial cells is regulated by various stimuli including cytokines and growth factors, thus the variants of those genes may modify the breast cancer risk. To evaluate the potential influences of TGF-1 T²⁹C and TNF- A²⁵²G gene polymorphisms on breast cancer risk, a case–control study was conducted in Korea.Methods. Histologically confirmed breast cancer cases (n = 560) and controls (n=509) with no previous history of cancer were recruited from three teaching hospitals in Seoul, Korea. Genotypes were determined by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusting for age, body mass index, education, parity, age at first full-term pregnancy, and family history of breast cancer. Results. The TGF-1 ²⁹C-allele containing genotypes posed an increased risk of breast cancer (OR=1.3, 95% CI=1.02–1.79), especially in postmenopausal women (OR=1.6, 95% CI=1.01–2.44). Similarly, the TNF- ²⁵²G-allele containing genotypes posed an increased risk of postmenopausal breast cancer (OR=1.7, 95% CI=1.09–2.55). The risk of postmenopausal breast cancer increased in parallel with the number of the risk genotypes (p for trend <0.01). When data were stratified by the presumed non-genetic risk factors, TGF-1 C-allele containing genotypes were found to increase breast cancer risk almost two-fold in postmenopausal women with greater than median body mass index (>22.8 kg/m²) (OR=1.9, 95% CI=1.04–3.37).Conclusion. The results of this study therefore suggest that polymorphisms of TGF-1 and TNF- genes may modify individual susceptibility to breast cancer in Korean women.     

A new <Emphasis Type="Italic">POT1</Emphasis> germline mutation—expanding the spectrum of <Emphasis Type="Italic">POT1</Emphasis>-associated cancers

Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access. Germline mutations in POT1 were recently shown to be associated with hereditary predisposition to melanoma. Our findings support a role of POT1 germline mutations in cancer predisposition beyond melanoma development, suggesting a broader phenotype of the POT1-associated tumor predisposition syndrome that might also include thyroid cancer as well as possibly other malignant tumors.     

Association between the <Emphasis Type="Italic">T27C</Emphasis> polymorphism in the <Emphasis Type="Italic">cytochrome P450 c17</Emphasis>α (<Emphasis Type="Italic">CYP17</Emphasis>) gene and risk factors for breast cancer

Mammographic density is associated with increased breast cancer risk and is influenced by sex hormones. A T27C polymorphism (alleles A1 and A2, respectively) in the 5 promoter region of CYP17 may be associated with elevated sex hormone levels. In a cross-sectional study of 181 pre- and 173 postmenopausal women, we examined the relationship of this polymorphism with mammographic density and other risk factors for breast cancer. Subjects were recruited across five categories of density. Risk factor and dietary information, anthropometric measures, and blood samples were obtained. Sex hormone, lipid, growth factor levels, and CYP17 genotypes were determined. CYP17 genotype was not associated with mammographic density levels before or after adjusting for risk factors for breast cancer. In premenopausal women, the A2 allele was associated with higher levels of dehydroepiandrosterone sulfate, and in postmenopausal women, with higher levels of total estradiol and lower levels of follicle stimulating hormone. Among premenopausal women, interactions were observed between CYP17 genotype and endogenous insulin levels as well as dietary variables associated with mammographic density. Our findings suggest that the CYP17 A2 allele is associated with hormone levels, and interacts with insulin levels and diet to affect breast density levels and potentially breast cancer risk.     

The <Emphasis Type="Italic">TP53</Emphasis> mutational spectrum and frequency of <Emphasis Type="Italic">CHEK2*1100delC</Emphasis> in Li–Fraumeni-like kindreds

Li–Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li–Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.     

A tandem duplication of <Emphasis Type="Italic">BRCA1</Emphasis> exons 1–19 through <Emphasis Type="Italic">DHX8</Emphasis> exon 2 in four families with hereditary breast and ovarian cancer syndrome

Background

Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer.

Methods

We conducted a case–control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12–13, ages 14–17, ages 18–22, ages 23–29 and ages 30–34 were determined using the Nurses’ Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12–34), during adolescence (ages 12–17) and during early adulthood (ages 18–34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status.

Results

Overall, there was no significant association between total physical activity and subsequent breast cancer risk (OR_{Q4 vs. Q1} = 1.01, 95% CI 0.69–1.47; P-trend = 0.72). Moderate physical activity between ages 12–17 was associated with a 38% decreased risk of premenopausal breast cancer (OR_{Q4 vs. Q1} = 0.62; 95% CI 0.40–0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause.

Conclusions

These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers.

Impact

Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.

     

Conversion of Fas-resistant to Fas-sensitive MCF-7 Breast Cancer Cells by the Synergistic Interaction of Interferon-<Emphasis Type="Italic">γ</Emphasis> and all-<Emphasis Type="BoldItalic">Trans</Emphasis>Retinoic Acid

Summary The membrane receptor Fas (Apo-1/CD95) is an important initiator of programmed cell death induced by anti-Fas antibody or Fas ligand. MCF-7 human breast cancer cells have low levels of Fas receptor (FasR) and are resistant to anti-FasR antibody mediated apoptosis, however two naturally occurring substances, interferon and all-trans retinoic acid (AT), act synergistically to enhance antiproliferative processes in these cells, suggesting this combination may also be an effective means for enhancing FasR expression. When this was studied, it was found that IFN-γ and AT in combination acted synergistically to induce expression of FasR mRNA and FasR protein in a time-dependent and dose-dependent manner. This induction required continuous protein synthesis, and STAT1 protein, but not PKR or TR1 protein, was induced in a manner quantitatively and temporally related to FasR protein induction, and consistent with STAT1 mediation of the synergistic effect of IFN-γ and AT on FasR expression. FasR-induced cells were resistant to stimulation of apoptosis by anti-FasR antibody, however treatment with cycloheximide rendered these cells sensitive to antibody-induced apoptosis, suggesting endogenous blockade to signaling. These cells did not express caspase 3, or FLIP_L, but strongly expressed the endogenous inhibitor of apoptosis Bcl-2, indicating a type II Fas signaling pathway. Expression of these proteins was not modulated by IFN/AT, however treatment of Fas-induced cells with Bcl-2 specific small interfering RNA (SiRNA) downregulated Bcl-2 protein expression and rendered these cells sensitive to the cytotoxic effects of anti-Fas antibody. These findings indicate that IFN-γ+AT in combination modulate Fas signaling and provide a novel mechanism for the promotion of cell death in breast cancer cells.     

c-<Emphasis Type="Italic">myc</Emphasis>, not <Emphasis Type="Italic">her</Emphasis>-2/<Emphasis Type="Italic">neu</Emphasis>, can predict the prognosis of breast cancer patients: how novel,how accurate,and how significant?

The predictive and prognostic implication of oncogene amplification in breast cancer has received great attention in the past two decades. her-2/neu and c-myc are two oncogenes that are frequently amplified and overexpressed in breast carcinomas. Despite the extensive data on these oncogenes, their prognostic and predictive impact on breast cancer patients remains controversial. Schlotter and colleagues have recently suggested that c-myc, and not her-2/neu, could predict the recurrence and mortality of patients with node-negative breast carcinomas. Regardless of the promising results, caution should be exercised in the interpretation of data from studies assessing gene amplification without in situ analysis. We address the novelty, accuracy and clinical significance of the study by Schlotter and colleagues.     

Glucosylceramide synthase upregulates <Emphasis Type="Italic">MDR1</Emphasis> expression in the regulation of cancer drug resistance through <Emphasis Type="Italic">cSrc</Emphasis> and β-catenin signaling

Background  

Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs. Polymorphisms of MDR1 disrupt the effects of P-glycoprotein antagonists and limit the success of drug resistance reversal in clinical trials. GCS converts ceramide to glucosylceramide, reducing the impact of ceramide-induced apoptosis and increasing glycosphingolipid (GSL) synthesis. Understanding the molecular mechanisms underlying MDR1 overexpression and how it interacts with GCS may find effective approaches to reverse drug resistance.     

<Emphasis Type="Italic">TP53</Emphasis> and <Emphasis Type="Italic">CDKN1A</Emphasis> mutation analysis in families with Li–Fraumeni and Li–Fraumeni like syndromes

Li–Fraumeni and Li–Fraumeni like syndromes (LFS/LFL) represent rare cancer–prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li–Fraumeni syndrome, and in 20–60 % of families with Li–Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.     

Detection of genetic instability at <Emphasis Type="Italic">HER-2/neu</Emphasis> and <Emphasis Type="Italic">p53</Emphasis> loci in breast cancer cells sing Comet–FISH

Summary A proportion of breast cancers acquire genetic alterations at 17q11.2–q12 (HER-2/neu), 20q13.2 (ZNF217 gene) and 17p13.1 (p53). We describe a unique technique (Comet–FISH) in which we documented relative genetic instability at p53 and HER-2/neu gene loci within a panel of malignant breast cancer cell lines (MCF-7; MDA-MB-468 and CRL-2336). Furthermore, Comet–FISH data were consistent with preferential repair of the p53 locus following gentoxic insult and suggest that this assay may be quite useful for the study of genetic instability.