Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan. MATERIALS AND METHODS: PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations. RESULTS: A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127, 0.8%). Besides, four in silico-predicted potentially functional mutations including three missense mutations and one 5' untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (≤ 30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated. CONCLUSION: Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan.

Different Patterns of Risk Reducing Decisions in Affected or Unaffected BRCA Pathogenic Variant Carriers / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate decision patterns to reduce the risks of BRCArelated breast and gynecologic cancers in carriers of BRCA pathogenic variants. We found a change in risk-reducing (RR) management patterns after December 2012, when the National Health Insurance System (NHIS) of Korea began to pay for BRCA testing and riskreducing salpingo-oophorectomy (RRSO) in pathogenic-variant carriers. MATERIALS AND METHODS: The study group consisted of 992 patients, including 705 with breast cancer (BC), 23 with ovarian cancer (OC), 10 with both, and 254 relatives of high-risk patients who underwent BRCA testing at the National Cancer Center of Korea from January 2008 to December 2016.We analyzed patterns of and factors in RR management. RESULTS: Of the 992 patients, 220 (22.2%) were carriers of BRCA pathogenic variants. About 92.3% (203/220) had a family history of BC and/or OC,which significantly differed between BRCA1 and BRCA2 carriers (p < 0.001). All 41 male carriers chose surveillance. Of the 179 female carriers, 59 of the 83 carriers (71.1%) with BC and the 39 of 79 unaffected carriers (49.4%) underwent RR management. None of the carriers affected with OC underwent RR management. Of the management types, RRSO had the highest rate (42.5%) of patient choice. The rate of RR surgery was significantly higher after 2013 than before 2013 (46.3% [74/160] vs. 31.6% [6/19], p < 0.001). CONCLUSION: RRSO was the preferred management for carriers of BRCA pathogenic variants. The most important factors in treatment choice were NHIS reimbursement and/or the severity of illness.

Progress in identifying genetic susceptibility genes for familial breast cancer / 中国肿瘤临床

Breast cancer is the most common malignant tumor in women. With the development of cell biology and molecular bio-technology, great progress has been made in the study of the pathogenesis of breast cancer. Familial breast cancer is closely related to the mutation of susceptible genes. Selected susceptible genes of breast cancer can be grouped into three categories: high-, medium-, and low-penetrance susceptible genes. The means of identifying the high-risk sites of pathogenic mutation and genetic polymorphism is the focus of research on the genetic predisposition of breast cancer.

Clinically Significant Unclassified Variants in BRCA1 and BRCA2 genes among Korean Breast Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls. MATERIALS AND METHODS: A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico. RESULTS: Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2. Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function. CONCLUSION: This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, ourfindings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.

Breast cancer conservation therapy in breast cancer patients with BRCA1/2 mutations / 国际外科学杂志

As an important surgical approach,breast cancer conservation therapy is still controversial in breast cancer patients with BRCA1/2 mutations.Since the risk of unilateral multiple and contralateral incidences is high in the familial breast cancer patients with BRCA1/2 mutations,breast cancer conservation therapy is not recommended but mastectomy and/or immediate mamoplasty.However,if carriers have a strong desire of breast cancer conservation therapy,it is feasible if they are fully informed the risks that may exist.At that time,we should need bilateral oophorectomy,tamoxifen therapy,and more interventions for the prevention of contralateral breast incidences.

Frequency of BRCA1 and BRCA2 Germline Mutations Detected by Protein Truncation Test and Cumulative Risks of Breast and Ovarian Cancer among Mutation Carriers in Japanese Breast Cancer Families / 한국유방암학회지

The purpose of this investigation is to study the frequency and penetrance of BRCA1 and BRCA2 germline mutations in Japanese familial breast cancer patients. Mutation analysis of BRCA1 and BRCA2 by protein truncation test was conducted on the 120 breast cancer patients (probands) with at least one breast cancer (site-specific breast cancer families, n=105) or one ovarian cancer (breast/ovarian cancer families, n=15) patient in their first-degree relatives. Eight BRCA1 (7.6%) and ten BRCA2 (9.5%) mutations were found in site-specific breast cancer families (n=105), and seven BRCA1 (46.7%) but no BRCA2 (0%) mutations were found in breast/ovarian cancer families (n=15). In site-specific breast cancer families, mutation frequency of BRCA1 and BRCA2 was high in families with more than three breast cancer patients (30%, 6/20), early onset (40< or = years old) breast cancer patients (41.1%, 14/34), or bilateral breast cancer patients (40%, 6/15). Cumulative incidence of breast cancer by age 70 was estimated to be 78% and 80% for BRCA1 and BRCA2 mutation carriers, respectively, and that of ovarian cancer was 40% and 0% for BRCA1 and BRCA2 mutation carriers, respectively. Family profiles are important determinants of risk for carrying a BRCA1 or BRCA2 mutation. Japanese women with BRCA1 mutation have a high risk of breast and ovarian cancer and those with BRCA2 mutation have a high risk of breast cancer but not ovarian cancer.

Familial Breast Cancer

Familial or hereditary breast cancer has genetic heterogeneity and is transmitted vertically in an autosomal dominant fashion. About 5 to 10% of breast cancers are caused by the inheritance of mutations in dominant susceptibility genes. We retrospectively reviewed 50 breast cancer patients from 44 families. These patients had treated their breast cancer at the Department of Surgery, Yonsei University College of Medicine, from 1981 to 1996. There were no statistically significant differences between the familial breast cancers and the sporadic breast cancers in such clinicopathologic characteristics as major complaint, tumor location, tumor size, metastasis to axillary lymph nodes, stage distribution, histology distribution and hormone receptor status. For familial camcers, the mean survival was 125 months, the overal 5-year survival rate was 85%, and the overall 5-year disease-free survival rate was 70%.