Case Of Bilateral Breast Cancer Research Articles

A case of super elderly synchronous bilateral primary breast cancer operated by local anesthesia and epidural anesthesia

A case of super elderly synchronous bilateral primary breast cancer operated by local anesthesia and epidural anesthesia

Clinical retrospective analysis of cases with multiple primary malignant neoplasms

The etiological factors, clinical characteristics, diagnosis, treatment strategies, and prognosis of multiple primary malignant neoplasms (MPMNs) were investigated in order to improve its diagnosis and therapy. Clinical data of 170 patients with MPMN who were admitted to the Oncology Department of the First Affiliated Hospital of Anhui Medical University from January 2004 to April 2010 were collected and analyzed retrospectively. The overall incidence of MPMNs was 2.25%. There were 167 cases with duplex primary cancers, 2 cases with triple primary cancers, 1 case with quadruple primary cancer, 46 synchronous MPMNs (SMPMNs), and 124 metachronous MPMNs (MMPMNs). There were 344 malignant neoplasms in the 170 MPMN patients, of which 161 were in the alimentary system, 48 in the respiratory system, 63 in mammary glands, 30 in the genital system, 7 in the urinary system, 23 in the head and neck, and the other 12 were in the brain, hematological system, and soft tissue. There were 22 cases of bilateral primary breast cancer and 41 cases of digestive MPMN. With a median survival time of 24 months, the 1-, 3-, and 5-year cumulative survival rates in the 170 patients were 68.8, 39.1, and 25.2%, respectively. The most common locations of MPMN were the alimentary system, mammary gland, and respiratory system. MPMN usually occurred in distinct organs of identical systems, conjugate organs, or identical organs. The survival rate of SMPMN was similar to that of MMPMN. There were differences in principles of treatment and diagnosis between MPMN and metastasis or recurrent cancers.

A case of synchronous bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character

We report a case of synchronous locally advanced bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character. The patient had presented bilateral breast cancer: the left breast cancer was hormone receptor negative, human epidermal growth factor receptor-2 (HER2) positive, and classified as T4bN1M0, stage IIIb, while the right was hormone receptor positive, HER2-negative, and classified as T4bN0M0, stage IIIb. We administered four cycles of anthracycline-based therapy followed by 12 weekly cycles of taxane with trastuzumab for neoadjuvant chemotherapy. We had achieved a significant left tumor reduction after each chemotherapy, but not right tumor. Bilateral modified radical mastectomies with axillary lymph-node dissection were performed. The therapeutic effect in the left was determined as a pathological complete response, in contrast to the right side. She has no recurrence for more than five years, though she had advanced cancer with oncologic emergency. This case could be an informative experience to understand the relation of tumor biology and response to systemic therapy.

A clinico-pathological study on cancer in sclerosing adenosis

Cancer in sclerosing adenosis includes the following 2 types: cancer genuinely arising from sclerosing adenosis and cancer arising near a sclerosing adenosis lesion and infiltrating into it. This study aimed to elucidate the features of the former by comparing both types. This study included 28 lesions in 27 cases of cancer in sclerosing adenosis for which surgery was performed during a 2-year period from January 2006 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We determined the proportions of cancer in sclerosing adenosis relative to the overall lesion of ductal carcinoma in situ. They were compared for 13 clinico-pathological factors by dividing the lesions into 2 groups: those involving cancer in 50 % or more (cancer in sclerosing adenosis predominant type-inner type) and those involving cancer in less than 50 % (cancer out of sclerosing adenosis predominant type-outer type). There were 20 lesions (71 %) of the inner type and 8 lesions (29 %) of the outer type. The comparison between the 2 types revealed significant differences in the following 3 factors. Bilateral breast cancer was observed in 5 cases (26 %) of the inner type and in none (0 %) of the outer type, indicating that there were significantly more cases of bilateral breast cancer for the inner type (p = 0.04). Regarding the subtypes of ductal carcinoma in situ, there were significantly more cases of the non-comedo type for the inner type (p = 0.002). Significantly fewer cases were positive for human epidermal growth factor receptor type 2 (HER2) for the inner type (p = 0.007). The results of this study suggest that cancer genuinely arising in sclerosing adenosis may often have biological features of bilateral breast cancer, non-comedo type in subtype, and being negative for HER2.

The prognosis of synchronous and metachronous bilateral breast cancer in Chinese patients

This study was undertaken to determine the differences in the clinicopathology and survival between synchronous bilateral breast cancer (sBBC) and metachronous bilateral breast cancer (mBBC). Additionally, we analyzed the risk factors for single tumors to develop as sBBC or mBBC. Of the 190 bilateral breast cancer (BBC) cases, 84 cases were sBBC and 106 were mBBC. We defined sBBC as two tumors that developed within 12 months, while mBBC was defined as two tumors that developed over more than 12 months. The peak age of onset of the first mBBC tumors was significantly younger than that of sBBC tumors (p = 0.001). There was a higher concordance rate of ER/ER positivity and PR/PR positivity in the first and second tumors of sBBC than mBBC. The two sBBC breast cancers had relatively similar hormone conditions because of the low rate of ER and PR transformation from positive to negative or vice versa. We determined that patients who presented with extracapsular extension (p = 0.008) and ER positivity (p = 0.001) tend to have synchronous cancers, while patients with 3+ HER2 were more likely to develop metachronous tumors. The prognosis for mBBC was better than that for sBBC when the survival time of mBBC was measured from the initial observation of the first tumors.

Analysis of complete response by MRI following neoadjuvant chemotherapy predicts pathological tumor responses differently for molecular subtypes of breast cancer

In the present study, clinical tumor response following neoadjuvant chemotherapy (NAC) was diagnosed by magnetic resonance imaging (MRI) and clinicopathological factors, including molecular subtypes at baseline, were analyzed for correlations with pathological tumor responses. In addition, clinicopathological factors were analyzed for a correlation with the MRI capacity to predict pathological complete response (pCR). Clinical tumor response evaluated by MRI following NAC was determined as a clinical CR (cCR) or a residual tumor. cCR was confirmed if no gadolinium enhancement or an enhancement equal to or less than that of glandular tissue was observed in any phase of the MRI. Pathological tumor responses following NAC were classified into grades 0 (no change) to 3 (no residual invasive cancer) according to criteria of the Japanese Breast Cancer Society. pCR was defined as grade 3 in the present study. Of 264 cases of invasive breast cancer in 260 patients (4 synchronous bilateral breast cancer cases), 59 (22%) were diagnosed by MRI following NAC as cCR and 98 (37%) were pathologically diagnosed as pCR. In terms of predicting pCR by MRI, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 44, 90, 73, 73 and 73%, respectively. Tumor size, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype and histological type were significantly correlated with pathological tumor responses. pCR rates increased in the following order: luminal/HER2-negative (14%), luminal/HER2-positive (32%), triple-negative (46%) and non-luminal/HER2-positive (73%) tumors. Sensitivity and specificity were the highest (60 and 100%, respectively) in triple-negative tumors. PPV decreased in the following order: triple-negative (100%), non-luminal/HER2-positive (92%), luminal/HER2-positive (46%) and luminal/HER2-negative (33%) tumors. In conclusion, MRI evaluation is useful for predicting pCR following NAC, particularly for triple-negative tumors.

Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02-4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel-Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.

Clinicopathological Features in Bilateral Breast Cancer

The frequency of bilateral breast cancer is 1.4-11.0% among all breast cancers. It can present as synchronous (SC) or metachronous (MC). Data regarding clinical course of bilateral breast cancer are scarce. In this study, we therefore evaluated demographic, pathological and clinical characteristics, treatments and responses in bilateral breast cancer cases; making distinctions between metachronous-synchronous and comparing with historic one-sided data for the same parameters. One hundred fifty bilateral breast cancer cases from ten different centers between 2000 and 2011 were retrospectively scanned. Age of the cases, family history, menopausal status, pathological features, pathological stages, neoadjuvant, surgery, adjuvant and palliative chemotherapy/radiotherapy were examined in the context of the first and second occurrence and discussed with reference to the literature. Metachronous and synchronous groups showed similar age, menopausal status, tumor type, HER2/neu expression; the family history tumor grade, tumor stage, ER-negativity rate, local and distant metastases rates, surgery, adjuvant chemotherapy application rates were identified as significantly different. Palliative chemotherapy response rate was greater in the metachronous group but median PFS rates did not differ between the groups. Although bilateral breast cancer is not frequent, MC breast cancer is different from SC breast cancer by having more advanced grade, stage, less ER expression, more frequent rates of local relapse and distant metastasis and better response to chemotherapy in case of relapse/metastasis.

Frequency of the CHEK2 1100delC mutation among women with early-onset and bilateral breast cancer

We read with great interest the recent Breast Cancer Research paper by Desrichard and colleagues [1] reporting the association between CHEK2 mutations and non-BRCA hereditary breast cancer risk. This report summarized the results of different case-control studies to provide an overview of CHEK2 1100delC mutation and susceptibility to early-onset breast cancer (EOBC) and bilateral breast cancer (BBC). We believe there are significant issues to note regarding the authors' study. To investigate the role of CHEK2 1100delC mutation in BBC susceptibility, Desrichard and colleagues performed a systematic review and pooled analysis based on five studies. Notably, another study that showed contradictory results indicating that the 1100delC mutation might not be a modifier in BBC [2] was not included in these analyses. Rashid and colleagues [3] have also shared their data, which failed to identify CHEK2 1100delC mutations among cases of BBC. Interestingly, the study by de Jong and colleagues [4] categorized individuals with BBC as unselected breast cancer cases. However, the BBC cases were included in the group of 192 patients identified with early-onset/familial breast cancer from an Irish study [5]. Hence, ongoing uncertainty exists and, in our opinion, the conclusion reached by Desrichard and colleagues may not be fully supported by the available data. An additional issue is the association between CHEK2 mutations and EOBC risk. Using the same search strategy as that of Desrichard and colleagues, we located three relevant case-control studies in PubMed comprising a total of 3,742 EOBC cases and 8,405 controls [6-8], which were not included in the pooled analyses. Furthermore, we have combined all of the studies on European populations into a new pooled analysis. By using a fixed-effect model, significant associations were found to be associated with CHEK2 1100delC mutation in patients with EOBC (odds ratio 3.14, 95% confidence interval 1.86 to 5.28). In conclusion, the association between CHEK2 1100delC mutation and BBC risk may be complex, and further studies will likely be needed to clarify the correlation of BBC and familial breast cancer characteristics. Similarly, further studies on EOBC-specific populations would be helpful for the purpose of better evaluating the association between CHEK2 1100delC mutation and EOBC risk.

一側が組織型の異なる多発癌であった同時性両側乳癌の1例

一側が組織型の異なる多発癌であった同時性両側乳癌の1例

Risk of breast cancer among Japanese women with a positive family history.

191 Background: Most breast cancer cases are sporadic, rather than associated with inherited gene mutations, such as BRCA1 and BRCA2. However, women with a family history of breast cancer are at increased risk of developing breast cancer compared to those women without any family history, even if they lack these gene mutations. Methods: We analyzed 10892 patients including bilateral breast cancer cases (total of 11398 breast cancers) who underwent surgery at our hospital between 1962 and 2009. We excluded 295 cases whose family history data were not available. Clinical and pathological differences between following patient groups were tested; 9528 patients or 9955 cancers (88%) with negative family history (FH-), 896 patients or 951 cancers (8%) who had at least one first-degree relative with breast cancer (1FH+), 468 patients or 492 cancers (4%) who had second-degree relative with breast cancer (2FH+), and 1364 patients or 1443 cancers (12%) with family history regardless of first- or second-degree relative (FH+). Significance was established at a p-value of < 0.05. Results: Among the family members, sisters were more likely to have treated for breast cancer (38% in FH+ group), followed by mothers (27%), aunts (26%), grandmothers (7%), and daughters (2%). The incidence of developing contralateral breast cancer was significantly higher in 1FH+ group, compared to patients in FH- and 2FH+ groups. No other factors showed any significant difference, including the incidence of cancer in other organs, pathological characteristics, and age of onset, although BRCA1 and BRCA2 mutation may be associated with increased risk of developing breast cancer at younger age. Outcome studies with available data did not show any significant difference in overall survival between FH+ and FH- patients. Conclusions: A Japanese woman with a positive family history has a higher risk of developing breast cancer than women without any close relatives with breast cancer, similar to the results reported in Western countries where prevalence of breast cancer is higher. Regular checkup of contralateral breast is important for those patients whose first-degree relatives have also been diagnosed with breast cancer.

Concurrent breast stroma sarcoma and breast carcinoma: a case report

IntroductionBreast cancer is one of the most important health problems in the world and affects a great number of women over the entire globe. This group of tumors rarely presents as bilateral disease and, when it does happen, normally occurs within the same histological type. We report a rare case of concurrent bilateral breast cancer with two different histology types, a breast carcinoma and a breast sarcoma, in a 42-year-old woman referred to our hospital.Case presentationA 42-year-old Caucasian woman admitted to our institute in August 1999, presented with a nodule in the left breast of 3.0 × 2.5 cm, and, in the right breast, one of 1.0 cm, suspected of malignancy and with a clinically negative armpit. Biopsies had revealed invasive mammary carcinoma (right breast) and sarcoma (left breast). She was submitted to bilateral modified radical mastectomy. A histological study showed an invasive mammary carcinoma degree II lobular pleomorphic type with invasion of seven of the 19 excised axillary nodes in the right breast and, in the left breast, a sarcoma of the mammary stroma, for which the immunohistochemistry study was negative for epithelial biomarkers and positive for vimentin. Later, she was submitted for chemotherapy (six cycles of 75 mg/m2 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy of the thoracic wall and axillary nodes on the left. Hormone receptors were positive in the tumor of the right breast, and tamoxifen, 20 mg, was prescribed on a daily basis (five years) followed by letrozole, 2.5 mg, also daily (five years). She presented no sign of negative evolution in the last consultation.ConclusionThe risk of development of bilateral breast cancer is about 1% each year within a similar histological type, but it is higher in tumors with lobular histology. In this case, the patient presented, simultaneously, two histologically distinct tumors, thus evidencing a rare situation.

Early Results of an Endoscopic Nipple-Sparing Mastectomy for Breast Cancer

BACKGROUND.: Endoscopic mastectomy has been reportedly associated with smaller scars and greater patient satisfaction; however, few reports on this topic have been made. The purpose of this retrospective study was to examine the early results of endoscopic nipple-sparing mastectomy (ENSM) and to investigate the safety of this procedure. METHODS.: Between January 2002 and December 2005, a total of 87 patients with breast cancer but without skin and nipple involvement, including two cases of bilateral breast cancer, underwent E-NSM. In case of bloody nipple discharge and suspicious extension near the nipple as assessed by magnetic resonance imaging, the major ducts within the nipple were cored (nipple coring). In other cases, nipple coring was not performed. RESULTS.: Of the 89 breasts in 87 patients, 42 had tumors of >2 cm and 80 were diagnosed as having invasive carcinoma. Lymph node involvement was observed in 36 procedures. The overall rate of nipple necrosis was 18% (16 of 89). The rate of nipple necrosis among the procedures with nipple coring was statistically higher than that among those without nipple coring (7 of 17, 41%, vs. 9 of 72, 13%) (P = .01). Nipple involvement was observed in 2.2% (2 of 89). After a median follow-up period of 52 months, distant metastasis was observed in nine cases; no local recurrences occurred in this series. CONCLUSIONS.: E-NSM is an oncologically safe procedure and an acceptable method in selected patients requiring a mastectomy. The higher rate of nipple necrosis may have been the result of a technical problem, indicating the need for continued improvement in nipple coring procedures.

Non-founder BRCA1 mutations in Russian breast cancer patients

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G, 5214C > T, 5236G > A, 5460G > T, 5622C > T) and one variant of an unknown significance (4885G > A). The pathogenic role of the 5236G > A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1–2 and 3–7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia.

Stage 2 Genome-Wide Association Study of Candidate Low Penetrance Genes Implicated in Breast Cancer Risk.

Abstract The risk of breast cancer in the first-degree female relatives of breast cancer cases is approximately double the risk in the general population. BRCA1 and BRCA2 account for less than 20% of this excess risk; the majority is probably due to the multiplicative effects of large numbers of low penetrance risk alleles. Genome-wide association studies (GWAS) have successfully identified 13 low-penetrance breast cancer risk alleles (Easton et al 2007, Hunter et al 2007, Stacey et al 2007, Zheng et al 2009, Ahmed et al 2009, Thomas et al 2009) but power calculations suggest that many more are still to be discovered.We have recently conducted a genome wide association study of 1,500 bilateral breast cancer cases, 200 cases with at least two affected first degree relatives and 1,450 controls from the 1958 birth cohort (WTCCC, 2007) using the Illumina HumanHap 370 chip. Based on these data and publicly available data from the Cancer Genetic Markers of Susceptibility (CGEMS) study we have selected 1,200 of the most significant SNPs to genotype in a stage 2 study comprising 5,500 breast cancer cases and 4,500 controls. All 13 of the known loci were replicated in this 2-stage analysis.Additional candidates at novel genomic loci are being genotyped in a replication study of 6,000 cases and 6,000 controls. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6136.

Early Results of an Endoscopic Nipple-Sparing Mastectomy for Breast Cancer

Endoscopic mastectomy has been reportedly associated with smaller scars and greater patient satisfaction; however, few reports on this topic have been made. The purpose of this retrospective study was to examine the early results of endoscopic nipple-sparing mastectomy (E-NSM) and to investigate the safety of this procedure. Between January 2002 and December 2005, a total of 87 patients with breast cancer but without skin and nipple involvement, including two cases of bilateral breast cancer, underwent E-NSM. In case of bloody nipple discharge and suspicious extension near the nipple as assessed by magnetic resonance imaging, the major ducts within the nipple were cored (nipple coring). In other cases, nipple coring was not performed. Of the 89 breasts in 87 patients, 42 had tumors of >2 cm and 80 were diagnosed as having invasive carcinoma. Lymph node involvement was observed in 36 procedures. The overall rate of nipple necrosis was 18% (16 of 89). The rate of nipple necrosis among the procedures with nipple coring was statistically higher than that among those without nipple coring (7 of 17, 41%, vs. 9 of 72, 13%) (P = .01). Nipple involvement was observed in 2.2% (2 of 89). After a median follow-up period of 52 months, distant metastasis was observed in nine cases; no local recurrences occurred in this series. E-NSM is an oncologically safe procedure and an acceptable method in selected patients requiring a mastectomy. The higher rate of nipple necrosis may have been the result of a technical problem, indicating the need for continued improvement in nipple coring procedures.

No Breast Cancer Association for Transforming Growth Factor-β Pathway Colorectal Cancer Single Nucleotide Polymorphisms

SMAD7 and GREM1 are signaling components on the transforming growth factor-beta pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis. Three variants within SMAD7 and two variants in CRAC1 (a colorectal cancer-associated region on chromosome 15 in which GREM1 is located) have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P < 10(-7)]. We genotyped these five variants in a series of 1,267 bilateral breast cancer cases and 900 controls to determine whether they are associated with breast as well as colorectal cancer risk. None of these single nucleotide polymorphisms were associated with breast cancer risk in our study and the 95% confidence limits of our data, pooled with data from the Cancer Genetic Markers of Susceptibility study, exclude per allele ORs of <0.94 or >1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site-specific.

Synchronous bilateral breast cancer in a male patient following hormone therapy for prostate cancer

We report an unusual case of bilateral, synchronous breast cancer in a male patient who had a history of estrogen therapy for prostate cancer. A 64-year-old Japanese man was diagnosed with T1N0M0 prostate cancer and received a total prostatectomy. Twenty months after the resection, the patient developed multiple bone metastases, and received radiation therapy, systemic chemotherapy, and hormone therapy for 15 months. After completing this treatment, he was diagnosed with T1N0M0 primary breast cancer in his left breast and underwent a modified mastectomy. Five months after the mastectomy he received systemic chemotherapy followed by estrogen therapy because of the progression of prostate cancer. Three months after this treatment, he was diagnosed with T1N0M0 primary breast cancer in his right breast. To the best of our knowledge, this is a rare case of synchronous bilateral male breast cancer following hormone therapy for prostate cancer.

Family History, Genetic Testing, and Clinical Risk Prediction: Pooled Analysis of CHEK2*1100delC in 1,828 Bilateral Breast Cancers and 7,030 Controls

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2 1100delC should be approximately 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be approximately 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2 1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P(trend) = 0.0003) and Finland (P(trend) = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2 1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2 1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2 1100delC and other moderate penetrance alleles in women with a family history of breast cancer.

Differences in outcome of young breast cancer patients according to BRCA1 mutation status

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G, 5214C > T, 5236G > A, 5460G > T, 5622C > T) and one variant of an unknown significance (4885G > A). The pathogenic role of the 5236G > A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1–2 and 3–7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia.