Whole breast radiotherapy in cN0 early breast cancer patients with pathological sentinel lymph nodes (pN1mic, pN1a) without axillary dissection: preliminary results of the observational LISEN trial.

PURPOSE: Axillary management remains unclear when sentinel lymph node (SLN) results are positive in cN0 patients with breast cancer (BC). The trial ACOSOG Z0011 represented a revolution with axillary lymph node dissection (ALND) omission in SLN+ patients, despite critiques regarding non-uniformity of radiation fields. We conducted an observational study (LISEN) where whole breast radiotherapy (WBRT) was planned with tangential fields without nodal irradiation in patients eligible for the Z0011 trial. METHODS: Inclusion criteria were female patients with histologically proven BC, cT1-2cN0, planned conservative surgery, no neoadjuvant therapy. Patients were stratified into two groups: micrometastatic (pN1mic, group 1) and macrometastatic (pN1a, group 2) lymph nodes. Tangential field WBRT was mandatory. Clinical outcomes were analysed, measured from surgery until the first event. RESULTS: In all, 199 patients underwent conservative surgery and SLN biopsy; 133 patients meeting criteria were analysed: 41 patients (30.8%) pN1mic and 92 (69.2%) pN1a. The 5­year disease-free survival (DFS) was 95.0% (85.9-100%) in group 1 and 93.0% (86.3-100.0%) in group 2 (p = 0.78). Overall survival (OS) was 100% (100-100%) in group 1 and 97.4% (92.4-100%) in group 2 (p = 0.74). For the whole cohort DFS and OS were 93.6% (88.2-99.4%) and 96.9% (91.5-100.0%), respectively. For groups 1 and 2, the 5­year outcomes were 5.0% (0.0-14.4%) and 2.3% (0.0-6.1%) for local recurrence (p = 0.51), and 6.2% (0.0-17.4%) and 7.0% (0.0-13.7%) for distant metastasis (p = 0.61), respectively. In group 1, regional recurrence (RR) and local regional recurrence (LRR) were 5.0% (0.0-14.1%; p = 0.13). In group 2, RR and LRR were 0.0% (0.0-0.0%). CONCLUSION: Our results showed good regional control in patients who met the Z0011 trial criteria. WBRT, without nodal surgery or RT, avoiding axillary morbidity, seems to be a good choice.

Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS® results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

Treatment Intensification for Locally Advanced Rectal Cancer: Impact on Pathological Complete Response and Outcomes.

AIM: Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC. RESULTS: Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively. CONCLUSION: Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.

Speed rate (SR) as a new dynamic index of melanoma behavior.

Melanomas are skin tumors that show a variety of biological behavior. Some develop very fast and some other grow extremely slow, with metastasis appearing, eventually, many years after the diagnosis. The number of mitoses in primary melanoma has been related to a more aggressive tumor and may have a potential as predictive factor for cutaneous melanoma survival. However, tumor mitotic rate is a static measure and in multivariate analysis on tumor survival, it has scored less than other tumor characteristics. We tried to evolve tumor mitotic rate from a static parameter to a time-dependent one. Similar to the already described growth rate (GR), we propose the speed rate (SR). SR is defined as the ratio of tumor mitotic rate to time to melanoma development. A prospective series of 345 patients with melanoma was investigated for the role of SR as predictive factor for sentinel lymph node (SLN) positivity and tumor progression. We calculated the best threshold for SR and GR to predict the risk of recurrence. Melanoma clinical and histological characteristics as well as GR were correlated in a multivariated analysis with SR. SR values >0.2 mitoses/month were associated with negative prognostic factors such as ulceration (82.8%), SLN positivity (80%), progression (82.8%), and death (85.7%). The association of GR > 0.3 mm/months and SR > 0.2 mitoses/month had a significant predictive value in terms of SLN positivity, progression, and recurrence-free survival. We propose SR as a new "dynamic" predictor of histological SLN positivity and melanoma recurrence risk. We think that he association with this new feature with GR may be helpful in improving the accuracy of predicted clinical outcome of patient especially with thin melanomas.

Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.

BACKGROUND: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT). METHODS: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered. RESULTS: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature (p = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant (p < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival (p = 0.027) and overall survival (p = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades (p < 0.05 for both). CONCLUSIONS: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.

Interleukin-30 Promotes Breast Cancer Growth and Progression.

The inflammatory tissue microenvironment that promotes the development of breast cancer is not fully understood. Here we report a role for elevated IL30 in supporting the breast cancer cell viability and invasive migration. IL30 was absent in normal mammary ducts, ductules, and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, IL30 was expressed frequently in breast cancer specimens where it was associated with triple-negative and HER2+ molecular subtypes. In stromal leukocytes found in primary tumors or tumor-draining lymph nodes, which included mainly CD14+ monocytes, CD68+ macrophages, and CD33+/CD11b+ myeloid cells, IL30 levels increased with disease stage and correlated with recurrence. A negative correlation was determined between IL30 expression by nodal stromal leukocytes and overall survival. In vitro studies showed that human recombinant IL30 upregulated expression of a pro-oncogenic program, including especially IL6 in both triple-negative and HER2+ breast cancer cells. In triple-negative breast cancer cells, IL30 boosted a broader program of proliferation, invasive migration, and an inflammatory milieu associated with KISS1-dependent metastasis. Silencing of STAT1/STAT3 signaling hindered the regulation of the primary growth and progression factors in breast cancer cells. IL30 administration in vivo fostered the growth of triple-negative breast cancer by promoting proliferation and vascular dissemination of cancer cells and the accumulation of intratumoral CD11b+/Gr1+ myeloid cell infiltrates. Overall, our results show how IL30 regulates breast cancer cell viability, migration, and gene expression to promote breast cancer growth and progression and its impact on patient outcome. Cancer Res; 76(21); 6218-29. ©2016 AACR.

Overexpression of PY1289-HER3 in sporadic pulmonary carcinoid from patients bearing MEN1 gene variants.

The present study aimed to investigate the expression of human epidermal growth factor receptors (HERs) (HER1/HER2/HER3/HER4) and their phosphorylated forms (p-HER1/p-HER2/p-HER3/p-HER4) in pulmonary carcinoids (PCs). HER and p-HER protein expression was assessed by immunohistochemistry on tissue microarrays in 37 specimens of sporadic PCs, 29 typical carcinoids (TCs) and 8 atypical carcinoids (ACs). When compared with the ACs, the TCs did not exhibit any differences in terms of HER/p-HER expression. The tumors of this study have previously been characterized for the expression of menin and the mutational status of menin 1 (MEN1), a gene strongly implicated in the pathogenesis of PCs. In the present study, it was found that the cytoplasmic ('disarrayed'), but not nuclear ('arrayed') expression of menin was positively correlated with HER3 (P=0.004), HER4 (P=0.015), p-HER1 (P=0.005), p-HER3 (P<0.001), and p-HER4 (P=0.001) expression. Moreover, HER3 and p-HER3 were found to be significantly more expressed in PCs with MEN1 variants, than in tumors with MEN1 wild-type (P=0.000 and P=0.025, respectively). These findings suggest the potential clinical use of HER inhibitors in the treatment of patients with PCs, particularly for individuals with p-HER3-positive PCs harboring MEN1 gene variants.

Diffuse large B-cell lymphoma of the colon with synchronous liver metastasis: a rare case report mimicking metastatic colorectal adenocarcinoma.

BACKGROUND: Primary colorectal lymphoma represents a rare minority among the colonic neoplasms. Early diagnosis is often difficult because of unspecific symptoms, with subsequent delays in diagnosis and management. We describe a rare case of colonic lymphoma presenting with synchronous liver metastasis. CASE PRESENTATION: A 70-year-old male with a 6-mo history of vague abdominal pain, constipation and melena was referred to our hospital. Computed tomography scan of abdomen revealed the presence of a mass along the proximal ascending colon. Colonoscopy biopsy showed external compression of the cecum with two ulcerations of mucosa, but it was not consistent for a definitive diagnosis. Because the difficulties in the preoperative pathological diagnosis, the high risk of bowel obstruction and the correlated hemorrhagic risk, the patient underwent a right hemicolectomy associated with locoregional lymphadenectomy and liver resection.The surgically resected right colon and liver tumors were all immunohistochemically diagnosed as diffuse large B-cell lymphomas (DLBCL). The patient refused any other antineoplastic treatment; he is alive and free of disease at 3 years after initial diagnosis. CONCLUSIONS: Primary colonic lymphomas represent a rare minority among the colonic neoplasms. Their correct pre-operative identification is crucial for the design of treatment. This case highlights the difficulty in diagnosing of primary colonic lymphoma. To our knowledge, this is the first report of a colonic lymphoma presenting with a colonic mass and a synchronous liver metastasis.

The Hippo transducer TAZ as a biomarker of pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy.

Activation of the Hippo transducer TAZ is emerging as a novel oncogenic route in breast cancer and it has been associated with breast cancer stem cells. Additionally, TAZ expression has been linked with HER-2 positivity. We investigated the association between TAZ expression and pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy.TAZ was assessed in diagnostic core biopsies by immunohistochemistry. To categorize samples with low TAZ and samples with high TAZ we generated a score by combining staining intensity and cellular localization. The pathological complete response rate was 78.6% in patients with low TAZ tumors and 57.6% in patients with high TAZ tumors (p=0.082). In HER2-enriched tumors there was no significant association between TAZ and pathological complete response, whereas in the luminal B subtype the pathological complete response rate was 82.4% in tumors with low TAZ and 44.4% in tumors with high TAZ (p=0.035). This association remained statistically significant when restricting our analysis to triple-positive tumors with expression of both estrogen receptor and progesterone receptor ≥ 50% (p=0.035). Results from this exploratory study suggest that the TAZ score efficiently predicts pathological complete response in Luminal B, HER2-positive breast cancer patients who received neoadjuvant chemotherapy and trastuzumab.

Long-term outcome of neoadjuvant endocrine therapy with aromatase inhibitors in elderly women with hormone receptor-positive breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs. METHODS: Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities. RESULTS: After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0-yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005). CONCLUSIONS: The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.

Surgical approach for nodular neck lesions mimicking primitive thyroid neoplasms Report of three cases.

AIM: The finding of a neck nodular lesion provides strong suspicion of primary thyroid malignancy. Direct extension into the thyroid parenchyma of carcinomas arising from pharynx, larynx, trachea or esophagus, nervous structures has been also observed in the minority of cases. The intent of our study is to present and discuss rare conditions presenting asymptomatic neck masses, with particular emphasis on pre-operative characteristics and diagnostic criteria. MATERIAL OF STUDY: In our retrospective analysis, we present three cases of nodular neck lesions that have mimicked primitive thyroid pathologies at the first diagnosis. RESULTS: A 53-mm nodular mass in the right thyroid lobe was observed in one patient. The definitive diagnosis was Castleman's disease. The second case presented a 20-mm hypoechoic lesion in the contest of a multinodular goiter. The pre-operative suspect was thyroid carcinoma with lymphnode metastases but the definitive histology documented an 'ancient schwannoma'. A further patient presented bilateral supra-clavear and cervical lymphnodes in a multinodular goiter, initially interpreted as thyroid carcinoma with loco-regional spread. After a total thyroidectomy and cervical lymphadenectomy, the definitive histology documented foci of poorly differentiated carcinoma in cervical lymphnodes and a multinodular goiter without atypical cellularity. The patient is considered to have an occult tumor, probably arising from the breast, and she was scheduled in an oncological program. CONCLUSIONS: Nodular neck lesions are frequently misdiagnosed as primitive thyroid nodules in the common clinical practice. In these rare conditions, surgical exploration is advocated to reach the definitive diagnosis, to indicate the most appropriate treatment and to avoid unnecessary thyroidectomy. KEY WORDS: Ancient Schwannoma, Castleman's disease, Nodular neck lesion, Thyroid nodule.

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice.

PURPOSE: The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice. METHODS: Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate. RESULTS: At Kaplan-Meier analysis, patients with surgical stage III disease were more likely to develop distant metastasis and die from breast cancer (p < 0.001). Luminal A and luminal B/HER2-negative patients had better prognosis; moreover, patients with hormone receptor (HR)-positive tumors had a significantly longer DRFS (p < 0.0049) and OS (p < 0.0001) compared with patients with HR-negative tumors as well as patients who underwent breast-conserving surgery (DRFS and OS: p < 0.001). In multivariate analysis, HR negativity (p < 0.001 for both DRFS and OS), mastectomy (DRFS: p = 0.009; OS: p = 0.05) and stage III disease (DRFS: p < 0.001; OS: p = 0.003) were associated with shorter DRFS and OS. CONCLUSIONS: HR negativity, mastectomy and pathological stage III disease are the variables independently associated with a worse outcome in our cohort of patients. These data are of high interest since they derive from a very heterogeneous group of patients, treated with different neoadjuvant/adjuvant regimens outside of clinical trials and with a long follow-up period.

Alterations of MEN1 and E-cadherin/ß-catenin complex in sporadic pulmonary carcinoids.

Pulmonary carcinoids, distinct in typical and atypical, represent 2-5% of all primary lung tumors. The aim of this study was to investigate the molecular alterations correlated with the development of this form of neoplasms. A collection of 38 paraffin-embedded apparently sporadic carcinoids was investigated, through a combined study, for protein expression/localization of menin, p53, ß-catenin and E-cadherin and for mutational analysis of the MEN1, TP53 and CTNNB1 genes. Menin was expressed in 71% of cases, with a prevalent cytoplasmic (c) localization, ß-catenin was expressed in 68.4% of cases, of which 36.8% with a membranous (m) and 31.6% with a cytoplasmic localization. Membranous E-cadherin immunoreactivity was detected in 84.2% cases, nuclear p53 expression in 5.3% of cases. Positive correlation was found between c-menin and c-ß-catenin expression (rho=0.439, P=0.008). In addition, m-ß-catenin showed a positive correlation with both c-ß-catenin and E-cadherin expression (rho=0.380, P=0.022 and rho=0.360, P=0.040, respectively). With regard to the E-cadherin/ß-catenin complex, we found also a significant positive correlation between c-menin and 'disarrayed' ß-catenin expression (rho=0.481, P=0.007). MEN1 gene variants were characterized in 34% of cases. c-menin was more highly expressed in tumors with MEN1 variants, compared to tumors without MEN1 variants (P=0.023). Three nucleotide variants of TP53 were also detected. This study confirms the involvement of the MEN1 gene in the development of sporadic pulmonary carcinoids, demonstrates the accumulation of menin in the cytoplasm, and indicates that the disarrayed pattern of the complex significantly correlates with c-menin accumulation.

Struma ovarii with follicular thyroid-type carcinoma and neuroendocrine component: case report.

Struma ovarii (SO) is a slow-growing ovarian neoplasm with thyroid tissue as its predominant component. It is an uncommon neoplasm, usually asymptomatic with an unknown risk of malignant transformation. Due to difficulties in assessing the rare biological nature and the discrepancies in the reported cases, a consensus on the appropriate treatment has not been definitively reached. A 50-year-old female was subjected to upper gut endoscopy which showed a 30-mm mass located in the gastric antrum, suggestive of mesenchimal tumor. Incidentally, a pelvic CT scan also documented a solid mass in the right adnexa, with morphological characteristics of ovarian neoplasm. The patient underwent gastrectomy, total hysterectomy, bilateral salpingo-oophorectomy with lymph node dissection, and omentectomy. Histology documented the presence of gastric cavernous angioma, and, in the right adnexa, foci of follicular thyroid-type carcinoma arising in SO with a well-differentiated neuroendocrine component.Here we report and discuss the clinical and morphological presentation of follicular thyroid-type carcinoma arising in SO. The neoplasm was discovered incidentally and had a favorable clinical outcome at 1-year follow-up.

16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer.

We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.