A study published in the journal Nature on May 2, 2016, has found nearly all the somatic genetic changes and mutations responsible for causing healthy breast tissue to mutate into cancer breast tissue, including 93 mutated cancer genes of which 31 were dominant, 6 rearrangement signatures, and 12 base substitution mutational signatures associated with deficient DNA repair and the function of BRCA1 and BRCA2 genes.

The research group was led by Wellcome Trust Sanger Institute and contributions were made by the European Bioinformatics Institute (EMBL-EBI).

The findings show that breast cancer genome is highly personalized. Dr Serena Nik-Zainal, the lead author, clinical fellow, and CDF group leader at the Sanger Institute, says that hopefully in future this research would help ‘profile individual cancer genomes’ so the treatment for each individual for every man and woman diagnosed with breast cancer can be identified. She explains that this research can bring us a step closer to personalized therapies and healthcare for cancer patients.

Professor Mike Stratton, the Director of Sanger Institute, also concurred that this huge study, ‘the largest of any one cancer type to date’, provides new clues into the genetic variations and in turn improves the chances of developing improved therapies.

The latest data from cancer.org suggests that in United States the risk for developing breast cancer is 1 out of 8 people and it is also the most common form of cancer in females (29%). In United Kingdom 54,000 new cases of breast cancer are diagnosed each year and almost 1,000 women die per month.

Study results, after analysis of three billion letters of people’s genetic code, revealed:

  • Six rearrangement signatures (a mutation leading to rearrangement of genetic material thus influencing the function of the material)
  • 12 base substitution (a kind of point mutation or single base modification that can cause a single nucleotide base replacement, substitution, insertion, or deletion of the genetic material in the form of DNA or RNA) mutational signatures
  • 93% mutated genes with 60 recessive, 31 dominant and 2 uncertain

The ten most frequently mutated genes were P53, PIK3CA, MYC, CCND1, PTEN, ERBB2, the ZNF703/FGFR1 locus, GATA3, RB1, and MAP3K1. These genes accounted for 62% of the drivers for breast cancer.

90 of the total cases had independent BRCA1 and BRCA2 mutations (60 germline, 14 somatic). The researchers hoped that these specific mutational signatures correlated with only either (specific) signature 3 or 5, “may be better biomarkers of defective homologous-recombination-based DNA double-strand break repair and responsiveness”, thus providing better basis for future diagnostics.

The study was initiated with extraction of breast cancer and normal tissue originating at peripheral blood lymphocytes and adjacent normal breast tissue and skin. Samples were collected from 560 individuals of United States, Europe, and Asia. The team also extracted total RNA from 268 of the same individuals. The materials were than analyzed under a preliminary pathological review and only samples with more than 70% tumor cells included for further analysis.

The researchers studied diseased breast tissue and looked for somatic mutations that encourage cancers to develop and grow in three different ways. Firstly, to identify mutated driver genes that can cause breast cancer, the sample along with additional 772 breast cancer whole-genome sequences from other institutions were analyzed.

Secondly, they also searched for the mutational signatures in each sample tissue using a three-step process of hierarchical de novo extraction, usage of mutational signatures to update the set of consensus signature, and evaluation of the contributions of each updated consensus signature.

Lastly, the scientists also analyzed the rearrangement signatures which occurred as ‘focal catastrophic events or focal driver amplicons’ using a piecewise constant fitting method.

This was important as a senior scientist and director at EMBL-EBI, Dr Ewan Birney explained that it is known for a while now that the genetic changes and their positions can dictate the course of treatment for a patient. Scientists have been trying for quite a while to figure out how and which part of the DNA (especially the DNA which does not code for anything specific) has a driving role in cancer development. This study provides us with the first largest overview of the genome, detailing reasons for cancer development and unexpected ways of characterization of these mutations in some breast cancers.

The collection, analysis, and reporting of the data was done without using statistical methods to predetermine the sample, without randomization, and without blinding the scientists during allocation, experimentation, and outcome assessment.

The study was funded through Breast Cancer Somatic Genetics Study or BASIS. BASIS, a European research project, is itself funded by European Community’s Seventh Framework Program.

BASIS forms a part of the International Cancer Genome Consortium (ICGC), a collaboration designed to comprehensively obtain descriptions of genetic changes in different and globally significant tumor types and subtypes.