Mutation Analysis of <em>BRCA1, BRCA2, PALB2</em> and <em>BRD7</em> in a Hospital-Based Series of German Patients with Triple-Negative Breast Cancer

<div><p>Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in <em>BRCA1</em>, <em>BRCA2</em>, <em>PALB2</em>, and <em>BRD7</em> genes. Microfluidic array PCR and next-generation sequencing was used for <em>BRCA1</em> and <em>BRCA2</em> analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of <em>PALB2</em> and <em>BRD7</em>, respectively. Truncating mutations in <em>BRCA1</em> were found in six patients, and truncating mutations in <em>BRCA2</em> and <em>PALB2</em> were detected in one patient each, whereas no truncating mutation was identified in <em>BRD7</em>. One patient was a double heterozygote for the <em>PALB2</em> mutation, c.758insT, and a <em>BRCA1</em> mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of <em>BRCA1</em> mutations. Triple-negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing.</p> </div

Truncating mutations in <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> among 40 TNBC patients.

<p>Truncating mutations in <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> among 40 TNBC patients. Mutations were designated according to the improved mutation nomenclature recommended by the Human Genome Variation Society (<a href="http://www.hgvs.org/mutnomen/" target="_blank">www.hgvs.org/mutnomen/</a>). AD = age at diagnosis, BC = breast cancer, OC = ovarian cancer, IHC = immunohistochemistry, n.a. = not applicable.</p>*<p>BIC database as from Sep 29, 2010 (<a href="http://research.nhgri.nih.gov/projects/bic/Member/index.shtml" target="_blank">http://research.nhgri.nih.gov/projects/bic/Member/index.shtml</a>), accessed on July 10, 2012.</p

Double heterozygosity for <i>BRCA1</i> and <i>PALB2</i> mutations.

<p>A case with digenic mutations in <i>BRCA1</i> (left) and <i>PALB2</i> (right). Left: Heterozygosity for mutation c.927delA in exon 10 of the <i>BRCA1</i> gene. Right: Heterozygosity for mutation c.758insT in exon 4 of the <i>PALB2</i> gene. The sense strand is shown in both electropherograms.</p

Comparison of age at diagnosis, Gleason Score and PSA at diagnosis between carriers of the truncating <i>TP53AIP1</i> variants and non-carriers.

a<p>: heterozygous.</p>b<p>: probands with available information for specified parameter.</p

Genotype specific odds ratio (OR), exact 95% confidence interval (CI 95%) and p-values of truncating <i>TP53AIP1</i> variants in case control comparisons.

a<p>: heterozygous.</p>b<p>: including 377 familial and 325 sporadic prostate cancer patients.</p

Association between SNP rs2180341 and breast cancer risk by estrogen receptor (ER) status among cases and controls of European ancestry, Breast Cancer Association Consortium (BCAC).

<p>Association between SNP rs2180341 and breast cancer risk by estrogen receptor (ER) status among cases and controls of European ancestry, Breast Cancer Association Consortium (BCAC).</p

Adjusted¹, weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between SNP rs2180341 genotype and breast cancer risk, in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).²

1<p>Adjusted for birth year and study.</p>2<p>Restricted to women of European descent.</p>3<p>MAF = Minor allele frequency.</p

Study-adjusted association between SNP rs2180341 and breast cancer risk by age among cases and controls of European ancestry, Breast Cancer Association Consortium (BCAC).

<p>Study-adjusted association between SNP rs2180341 and breast cancer risk by age among cases and controls of European ancestry, Breast Cancer Association Consortium (BCAC).</p

SNP rs2180341 per-allele hazard ratios (HRs) and 95% confidence intervals (CIs) among Consortium of Investigators of Modifiers of <i>BRCA1/2</i> (CIMBA) in A. <i>BRCA1</i> mutation carriers B. <i>BRCA2</i> mutation carriers.

<p>Studies are weighted and ranked according to the inverse of the between-study and within study variation of the log odds ratio, which is also represented by the size of the shaded box around the study-specific point estimate. The solid line indicates the OR = 1 and the dashed lined indicates the summary OR of all studies. A description of the study acronyms can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035706#pone.0035706.s001" target="_blank">Supporting Information S1</a>.</p

Forest plot of SNP rs2180341 per-allele odds ratios (ORs) and 95% confidence intervals (CIs) with the risk of breast cancer among studies from Breast Cancer Association Consortium (BCAC) breast cancer cases and controls of European ancestry.

<p>Studies are weighted and ranked according to the inverse of the between-study and within study variation of the log odds ratio, which is also represented by the size of the shaded box around the study-specific point estimate. The solid line indicates the OR = 1 and the dashed lined indicates the summary OR of all studies. A description of the study acronyms can be found in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035706#pone.0035706.s001" target="_blank">Supporting Information S1</a>.</p