Genotype inBRCA-associated Breast Cancers

Abstract

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3′) location for mutations compared to the upstream (5′) mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA-associated breast cancers and whether or not there was a genotype-phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty-four patients with BRCA1-associated breast cancer and 109 patients with BRCA2-associated breast cancer were identified. Among patients with BRCA1-associated cancers, 86 (52%) had mutations in the 5′ half of the gene. Among patients with BRCA2-associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1-associated tumors were more likely to be ER/PR- than BRCA2-associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2-associated cancers based on mutation location. In this single-institution study, over half of BRCA1-associated and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.

Primer in Genetics and Genomics, Article 5—Further Defining the Concepts of Genotype and Phenotype and Exploring Genotype–Phenotype Associations

“…Mutations in one or both of these genes are common in certain populations. For example, researchers first identified the genotypes BRCA1 187delAG (where an adenine and guanine nucleotide are deleted from the DNA sequence), BRCA1 5385insC (where a cytosine nucleotide is inserted into the sequence) and BRCA2 6147delT (where a thymine nucleotide is deleted) in Ashkenazi Jews (Meric-Bernstam et al, 2013). Phenotypically, individuals with these genotypes, especially those involving BRCA1 mutations, are at an increased risk of being diagnosed with breast cancer at a younger age than those with a wild-type genotype, and their tumors are more likely to be estrogen, progesterone and HER2 negative, which confers challenges in treatment selection as hormonal blockade and biological therapy with trastuzumab are not indicated in these “triple negative” cases (Tung et al., 2014).…”

Identification of estrogen receptor proteins in breast cancer cells using matrix-assisted laser desorption/ionization time of flight mass spectrometry (Review)

“…The balance between coregulators is crucial for regulation of gene transcription by ERα ( 25 ). Overexpression of coactivators, for example coactivator-associated arginine methyltransferase 1, may also increase the expression of ERα target genes involved in breast tumor cell differentiation and proliferation ( 26 ), including breast cancer (BRCA) 1 and BRCA2 genes ( 27 ). In addition, reduction of ERα spliced variant 46 (46 kDa) and 36 (36 kDa) mRNA levels have been observed in colon tumors ( 28 ) and overexpression of ERα36 has been observed in gastric ( 29 ) and endometrial cancers ( 30 ).…”

The audacity of interpretation: Protecting patients or piling on?

“…This aspect of l'affaire 23andMe was a surprise: recent criticism of the company's assessment of a single pharmacogenetic locus notwithstanding ( Brownstein et al, 2014 ), it seems to me that most—and arguably the most robust—criticisms of the substance of DTC genetics companies' offerings have been directed at their speculative and often contradictory lifetime risk estimates for complex diseases derived from genome-wide association studies ( Peikoff, 2013 , Ng et al, 2009 , Janssens et al, 2011 , Kido et al, 2013 , Kalf et al, 2014 ). Thus, for the FDA to attack the company's assessment of the genetic basis of warfarin metabolism or BRCA alleles seemed less convincing: would any self-respecting surgical oncologist subject a woman to a radical mastectomy and/or oophorectomy based on nothing more than a $99 direct-to-consumer test that examined three known pathogenic alleles out of many hundreds ( Meric-Bernstam et al, 2013 )? This would be akin to an ob-gyn forgoing both a blood hCG pregnancy test and a pelvic exam because her patient had already reported a positive home pregnancy test.…”