Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Abstract

We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

“…By adapting the method developed by Alexandrov and colleagues to assign specific signatures to mutational processes in human tumors 16 , we identified mutational signatures contributing to somatic mutations in brain tumors developing in BRCA2/p53, Lig4/p53 and XRCC4/p53 deficient mice (Figure 4d). Interestingly, all tumors developing in a context of cNHEJ inactivation displayed contributing proportions of signature 3 (associated with a failure of DNA DSB repair by HR 17 ) in the same range as tumors from BRCA2/p53 animals and from a human MB occurring 7 in a patient with biallelic inactivation of BRCA2. The contribution of mutational signature 3 in the context of functional HR but inactive cNHEJ may point to a novel etiology for signature 3, namely consequences from excessive levels of DSBs and from the inability of the repair system to cope with high DNA damage, rather than necessarily pre-existing HR defect.…”

Germline mutation contribution to chromosomal instability

“…In addition to base substitution signatures, signatures of rearrangement mutational processes such as deletions, inversions, tandem duplications and interchromosomal translocations have recently been reported for breast cancer (Nik-Zainal et al 2016). In this study, the authors alluded to an improved diagnostic utility for HR deficiency in breast tumors by merging base substitution and rearrangement mutational signatures for a more comprehensive and characteristic profile (Nik-Zainal et al 2016).…”

“…It has been shown that defects in the maintenance of genomic DNA integrity are strongly associated with a distinctive few of these reported mutational signatures. Importantly, tumors with HR deficiency such as breast, ovarian and pancreatic tumors with germline/somatic mutations in BRCA1 or BRCA2 are shown to harbor mutational signature 3 (Alexandrov et al 2013, Nik-Zainal et al 2016, whereas signatures 6, 20 and 26 are frequently found in microsatellite unstable tumors, such as colorectal and uterine cancers with defective DNA mismatch repair (Alexandrov et al 2013, Forbes et al 2017. Moreover, as seen in breast cancer, it was possible to distinguish tumors with germline mutations in susceptibility genes through differences in the relative contributions of each component signature (Nik-Zainal et al 2012, Alexandrov & Stratton 2014.…”

“…Moreover, as seen in breast cancer, it was possible to distinguish tumors with germline mutations in susceptibility genes through differences in the relative contributions of each component signature (Nik-Zainal et al 2012, Alexandrov & Stratton 2014. In addition to base substitution signatures, signatures of rearrangement mutational processes such as deletions, inversions, tandem duplications and interchromosomal translocations have recently been reported for breast cancer (Nik-Zainal et al 2016). In this study, the authors alluded to an improved diagnostic utility for HR deficiency in breast tumors by merging base substitution and rearrangement mutational signatures for a more comprehensive and characteristic profile (Nik-Zainal et al 2016).…”

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…La plupart des maladies néoplasiques fréquentes se voient ainsi démembrées en de multiples entités moléculaires de pronostic différent, et requérant des traitements potentiellement différents (1)(2)(3)(4)(5)(6). La gestion clinique de cette complexité reste à ce stade largement empirique, guidée par les essais cliniques « basket » et « umbrella », « paniers » et « parapluie » actuellement en cours de réalisation et décrits dans ce document.…”