Mutation analysis of <Emphasis Type="Italic">PALB2</Emphasis> in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>-negative breast and/or ovarian cancer families from Eastern Ontario,Canada

Background

PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.

Methods

The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.

Results

We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.

Conclusions

PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.     

Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer

BACKGROUND: The genetic basis of susceptibility to prostate cancer (PRCA) remains elusive. Mutations in BRCA2 have been associated with increased prostate cancer risk and account for around 2% of young onset (<56 years) prostate cancer cases. PALB2 is a recently identified breast cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures. This functional relationship made PALB2 a candidate PRCA susceptibility gene. METHODS: We sequenced PALB2 in probands from 95 PRCA families, 77 of which had two or more cases of early onset PRCA (age at diagnosis <55 years), and the remaining 18 had one case of early onset PRCA and five or more total cases of PRCA. RESULTS: Two previously unreported variants, K18R and V925L were identified, neither of which is in a known PALB2 functional domain and both of which are unlikely to be pathogenic. No truncating mutations were identified. CONCLUSIONS: These results indicate that deleterious PALB2 mutations are unlikely to play a significant role in hereditary prostate cancer.     

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case–control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2–78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8–217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.     

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context

Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC.

The BRCA2 c.9004G>A (E2003K) variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent

Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35-55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28-84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.     

Phase II trial of liposomal daunorubicin in malignant pleural mesothelioma

Background:To assess the response rate, toxicity and survival in patients with malignant pleural mesothelioma treated with liposomal daunorubicin. The study design allowed for dose escalation pending toxicity. Patients and methods:Liposomal daunorubicin (DaunoXome, Nexstar, USA) 120 mg/m² was administered every 21 days to a maximum of 6 cycles. Patients had to have histologically-proven malignant pleural mesothelioma. Patients were all chemotherapy-naïve with ECOG performance status 0–2. Results:Fourteen patients were enrolled. There were no objective or symptomatic responses though nine patients (64%) had stable disease on therapy. Myelosuppression was the major toxicity with 9 of 11 patients evaluable for toxicity experiencing grade 3 or 4 neutropenia. Other toxicities seen in at least 30% of patients included grade 3 infection and grade 2 nausea and vomiting. The median overall survival by intention-to-treat analysis was 6.1 months from the time of first treatment. The median duration of stable disease from time of first treatment for patients not progressing on therapy was 5.1 months. Conclusions:Liposomal daunorubicin 120 mg/m² has no useful clinical activity in patients with malignant pleural mesothelioma. Toxicity was substantial with most patients experiencing at least one episode of grade 3 or 4 neutropenia. Liposomal daunorubicin cannot be recommended for patients with malignant pleural mesothelioma.     

19. Male breast cancer: aetiology,genetics and clinical management

Male breast cancer (MBC) is a rare disease with an older average age of presentation than in women. Predisposing factors include increased exposure to oestrogen and being a carrier of a BRCA2 mutation. Most MBC is ductal and the majority are oestrogen receptor positive. Modified radical mastectomy is the treatment of choice for local disease and adjuvant radio-, hormonal and chemotherapy should all be considered. Stage for stage, the prognosis for MBC is similar to that for female breast cancer. Despite a wealth of small retrospective studies on MBC, its rarity means there is a lack of prospective randomised controlled treatment trials, which needs to be addressed if significant advances are to be made in the treatment of this unusual and challenging disease.