Serena Masciari

Germline E‐cadherin mutations in familial lobular breast cancer

Background: The cell surface glycoprotein E-cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well established as the defects underlying hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in patients with LBC in non-HDGC families. This study aimed to investigate the frequency of germline CDH1 mutations in patients with LBC with early onset disease or family histories of breast cancer without DGC. Methods: Germline DNA was analysed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before the age of 45 years, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was amplified using PCR and screened for mutations using DHPLC and sequencing. Results: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one woman who had LBC at the age of 42 years and a first degree relative with invasive LBC. Conclusions: Germline CDH1 mutations can be associated with invasive LBC in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype. Clarification of the cancer risks in the syndrome is essential.

Hereditary diffuse gastric cancer: association with lobular breast cancer.

Hereditary diffuse gastric cancer (HDGC) has been shown to be caused by germline mutations in the gene CDH1 located at 16q22.1, which encodes the cell–cell adhesion molecule, E-cadherin. Not only does loss of expression of E-cadherin account for the morphologic differences between intestinal and diffuse gastric cancer (DGC) variants, but it also appears to lead to distinct cellular features which appear to be common amongst related cancers that have been seen in the syndrome. As in most hereditary cancer syndromes, multiple organ sites may be commonly affected by cancer, in HDGC, lobular carcinoma of the breast (LBC) and possibly other organ sites have been shown to be associated with the familial cancer syndrome. Given the complexity of HDGC, not only with regard to the management of the DGC risk, but also with regard to the risk for other related cancers, such as LBC, a multi-disciplinary approach is needed for the management of individuals with known CDH1 mutations.

F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Screening in Li-Fraumeni Syndrome

CONTEXT Individuals with Li-Fraumeni syndrome (LFS) have an inherited cancer predisposition to a diverse array of malignancies beginning early in life; survivors of one cancer have a markedly elevated risk of additional primary tumors. The underlying genetic defect in the majority of the families is a germline mutation in the TP53 tumor suppressor gene. The diversity of tumors and rarity of families have contributed to the difficulty in devising effective screening recommendations for members of LFS kindreds. OBJECTIVE To gather preliminary data with which to evaluate F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging as a potential surveillance modality to detect early malignancies in asymptomatic members of LFS kindreds. DESIGN, SETTING, AND PARTICIPANTS Members of LFS families with documented germline TP53 mutations or obligate carrier status, no history of cancer within 5 years of enrollment, and no symptoms of cancer or ill-health were offered FDG-PET/CT scanning as a screening test in a comprehensive US cancer center from 2006 to 2007. Scans were initially reviewed clinically, then centrally reviewed by an expert radiologist. MAIN OUTCOME MEASURE The primary outcome was the detection of new primary cancers using FDG-PET/CT scanning. RESULTS Of 15 individuals, baseline FDG-PET/CT scan identified asymptomatic cancers in 3 (20%). Two individuals had papillary thyroid cancers (stage II and stage III) and one individual had stage II esophageal adenocarcinoma. CONCLUSIONS These preliminary data provide the first evidence for a potential cancer surveillance strategy that may be worthy of further investigation for patients with LFS. Concerns about radiation exposure and other challenges inherent in screening high-risk patients will require further consideration.

Gastric cancer in individuals with Li-Fraumeni syndrome

Purpose: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome.Methods: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens.Results: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24–74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.Conclusions: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.

Basal Cytokeratin and Epidermal Growth Factor Receptor Expression Are Not Predictive of brca1 Mutation Status in Women With Triple-negative Breast Cancers

Background Over 80% of breast cancers in women with germline BRCA1 mutations are estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative (“triple negative”) and most of these have a basal-like phenotype by expression profiling and immunophenotypic analysis. However, whether or not expression of biomarkers characteristic of basal-like breast cancers helps to define a subset of women with triple-negative breast cancers who are likely to harbor BRCA1 mutations is an unresolved issue. Methods We randomly identified 165 women from the Dana-Farber/Harvard Cancer Center SPORE annotated specimen bank with primary invasive, triple-negative breast cancers. Tissue microarrays were constructed by obtaining triplicate 0.6 mm cores from available paraffin blocks from 130 cases: only unstained slides were available for immunostaining from 35 cases. Slides cut from the tissue microarrays and the unstained slides were immunostained for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (to confirm triple-negative status) and for several markers that have been reported to be useful in defining the basal-like phenotype, including basal cytokeratins CK5/6, CK14, and CK17 and epidermal growth factor receptor (EGFR). Full sequencing analysis for BRCA1 germline mutations was performed on blood specimens from all cases. The final study population consisted of 144 cases in which (1) triple-negative status was confirmed; (2) there was sufficient material for analysis of basal cytokeratins and EGFR; and (3) germline BRCA1 mutation status was known. Results Among these triple-negative breast cancer cases, 97 (67%) expressed one or more basal cytokeratins and 102 (71%) showed EGFR expression. Basal cytokeratin expression was detected in 65% of the tumor from the 20 BRCA1 mutation carriers and in 68% of the cancers from women without mutations (P=NS). EGFR expression was identified in a similar proportion of tumors from women with and without BRCA1 mutations (75% vs. 72%, P=NS). Conclusions Basal cytokeratin and EGFR expression are both highly prevalent among triple-negative breast cancers. The frequency of expression of basal cytokeratins and EGFR was similar in women with and without BRCA1 mutations. Therefore, although the expression of basal cytokeratins and/or EGFR can be used to identify triple-negative breast cancers that have a basal-like phenotype, expression of these markers alone is not sufficient to distinguish which women with triple-negative breast cancers are likely to harbor BRCA1 germline mutations.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers

Background Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. Method To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. Results No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. Conclusion Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Quality or quantity in the management of hereditary ovarian cancer risk: Is it really a trade-off?

Women with increased probability of developing ovarian cancer face the dilemma of how best to manage their risk. Lifetime ovarian cancer risk is increased in women who carry germline mutations in the hereditary breastovarian cancer susceptibility genes BRCA1 (40% to 60%) and BRCA2 (15% to 20%), 1 and in the hereditary nonpolyposis colon cancer–associated genes (10% to 12% risk), 2 as well as in familial clusters not attributable to known genes. Current options for early detection of ovarian cancer include serial transvaginal ultrasound examinations and serum CA-125 determinations, but the sensitivity of these methods remains disappointing. 3 Risk-reducing salpingooophorectomy (RRSO) has been shown to reduce the risk of ovarian and fallopian tube cancers in women with BRCA1/2 mutations by more than 90%. 4,5 When performed in premenopausal BRCA1/2 mutation carriers, RRSO also reduces the risk of breast cancer by nearly 50%, 4,5 consistent with older data documenting a substantial reduction in breast cancer risk in normal-risk women conferred by surgical menopause before age 40 years. 6 Based on such data, RRSO is recommended by several groups for BRCA1/2 mutation carriers following completion of child-bearing after age 35 to 40 years. 7,8 However, medical management strategies remain suboptimal for the consequences of premature menopause, including vasomotor symptoms, and sexual and skeletal health. Therefore, premenopausal women with high ovarian cancer risk must prepare to take on early menopause as the very significant price of effective risk reduction. In this issue of the Journal of Clinical Oncology, Madalinska et al 9 present a snapshot of the quality of life (QOL) among high-risk women who have undergone RRSO, compared with those who are relying on surveillance to manage their increased ovarian cancer risk. In their cross-sectional study, the investigators used mailed surveys to collect data from women identified from gynecologic practices across the Netherlands who had increased ovarian cancer risk because of hereditary familial breast and ovarian cancer syndrome. The analysis was conducted on a large sample of 846 high-risk women, among whom 369 (44%) had undergone RRSO, while 477 (56%) were following surveillance programs (pelvic examination, transvaginal sonography, and serum CA-125 determination). A number of validated QOL measures were included in the instrument. The findings should be reassuring to women considering prophylactic surgery. Overall QOL measured using four of eight subscales of the SF36 Health Survey was not different between the two groups. Women who had undergone surgery had less cancer worry (P .001), and in multivariate analysis, less specific worry about ovarian cancer risk (P .001) for themselves and their family members (P .0001) than did women who had chosen screening. However, women who had chosen surgery also reported significantly more endocrine symptoms and sexual dysfunction than women who had opted for gynecologic screening, despite similar levels of sexual activity, and also despite hormone therapy. Finally, 97% of women who had undergone RRSO reported satisfaction with surgery, while 33% of the women in the surveillance group reported their intention to have surgery in the future. The authors recommend that counseling for women about prophylactic ovarian surgery include both reassurance that most women report good QOL after surgery, with relief from cancer worry, and caution that menopause symptoms will often be problematic. The findings of Mandalinska et al are consistent with the existing literature 10-12 and will resonate with providers caring for women facing these decisions. A significant strength of this study compared with prior reports is the

Screening with whole‐body magnetic resonance imaging in pediatric subjects with Li–Fraumeni syndrome: A single institution pilot study

Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood‐onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole‐body magnetic resonance imaging (WB‐MRI) may provide an acceptable method for early cancer detection.