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Page 234 Crisafulli et al. Cancer Drug Resist 2019;2:225-41 I http://dx.doi.org/10.20517/cdr.2018.008

efforts aim at sequencing up to 500 clinically well-annotated tumor groups, with the projected generation
of an enormous amount of genomic data. To date, the Cancer Genome Atlas has already published initial
analyses of glioblastomas and ovarian, colorectal, and breast cancers, identifying a number of deregulated
genes that may set the stage for the development of targeted therapies and for associated pharmacogenetic/
pharmacogenomic biomarkers.

[1]
The shift to knowledge-driven cancer treatment requires novel classification strategies of cancer endotypes .
Improvements in 2nd and 3rd generation NGS [Supplementary Tables 2 and 3] have paved the way for the
[61]
use of pharmacogenomics testing at a whole-genome level .

Clinical oncology utilization of current knowledge on cancer hereditary genetics (ascopubs.org/toc/edbk/
current) largely focuses on highly penetrant genes, which can account for a considerable fraction of a given
cancer risk. Main examples comprise mismatch DNA repair genes, for Lynch syndrome, BRCA-1, -2, PALB2
for ovarian, breast and prostate cancer, TP53 for Li-Fraumeni syndrome (www.cancer.gov/about-cancer/
causes-prevention/genetics/genetic-testing-fact-sheet#q4) and are extensively treated in other chapters of this
journal issue.

[27]
Cancer genomics can extensively identify and quantify cancer inherited risk . Tumor DNA sequencing
and comparison to the germline genome may identify variants associated with hereditary predisposition to
cancer. Such an ability to achieve high-throughput genotyping often surpasses, though, our current ability
to interpret and appropriately apply the vast amounts of data that are generated. Although known hereditary
cancer susceptibility syndromes are more than one hundred, mutations in high-penetrance genes explain
[79]
only a fraction of the heritability of human cancers [Figure 2] .
GWAS have been conducted on nearly all common cancers. However, given the modest effect size for most
risk variants, the clinical utility of genomic profiling for risk stratification based on GWAS data has been
limited. A large international consortium study led to the identification of 49 new loci for breast cancer,
26 for prostate cancer, and 8 for ovarian cancer. Extension of such approaches may allow better genetic
susceptibility models of cancer risk.

Despite such extensive research, only approximately 30% of familial breast cancer risk is explained by known
genetic factors. WES in affected family members from 13 breast cancer families identified two families with
mutations in XRCC2, including a protein-truncating change and a probable deleterious missense mutation.
Another Fanconi pathway gene, SLX4 was found in only one of ≈700 BRCA-negative breast cancer kindreds.
Most recently, a large pooled NGS study focusing on DNA repair pathways identified mutations in the p53-
inducible protein phosphatase PPM1D as occurring mosaically in individuals with predisposition to breast
and ovarian cancers. SNP-associated risk analysis identified a frameshift mutation in the BRIP1 Fanconi
pathway gene, with an odds ratio of 8.1 for ovarian cancer. As indicated above, the identification of genes
that are associated with homologous recombination DNA-repair has a role for targeted therapies, such as
poly (ADP-ribose) polymerase inhibitors. WGS in families with multiple adenomas and/or colorectal cancer
recently identified heterozygous POLE and POLD1 germline variations. GREM1 is the first gene to have
been implicated in the genetic etiology of hereditary mixed polyposis syndrome. In prostate cancer, NGS
of linkage regions on chromosome 17 helped to identify a mutation in the homeobox gene HOXB13 as a
prostate cancer driver and potential therapy target.

REPOSITIONING OF CANCER-DRIVING MUTATIONS AND OF CORRESPONDING THERAPY
TARGETS
NGS screening programs of cancer genomes have surprisingly led to the identification of cancer-driving
mutations in tumor types that were essentially unrelated to the ones under investigations. As several driver