The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.

/pdf/parp-inhibitors-clinical-relevance-mechanisms-of-action-and-19cz8b414u.pdf

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance.

An epidemiologic study was conducted to determine whether polymorphisms in DNA repair genes modify the association between breast cancer risk and exposure to ionizing radiation. Self-reported exposure to ionizing radiation from medical sources was evaluated as part of a population-based, case-control study of breast cancer in African-American (894 cases and 788 controls) and White (1,417 cases and 1,234 controls) women. Genotyping was conducted for polymorphisms in four genes involved in repair of radiation-induced DNA damage, the double-strand break repair pathway: X-ray cross-complementing group 3 (XRCC3) codon 241 Thr/Met, Nijmegen breakage syndrome 1 (NBS1) codon 185 Glu/Gln, X-ray cross-complementing group 2 (XRCC2) codon 188 Arg/His, and breast cancer susceptibility gene 2 (BRCH2) codon 372 Asn/His. Allele and genotype frequencies were not significantly different in cases compared with controls for all four genetic polymorphisms, and odds ratios for breast cancer were close to the null. Combining women with two, three, and four variant genotypes, a positive association was observed between breast cancer and number of lifetime mammograms (P(trend) < 0.0001). No association was observed among women with zero or one variant genotype (P = 0.86). Odds ratios for radiation treatments to the chest and number of lifetime chest X-rays were slightly elevated but not statistically significant among women with two to four variant genotypes. The study has several limitations, including inability to distinguish between diagnostic and screening mammograms or reliably classify prediagnostic mammograms and chest X-rays in cases. Prospective studies are needed to address whether common polymorphisms in DNA repair genes modify the effects of low-dose radiation exposure from medical sources.

https://cebp.aacrjournals.org/content/cebp/14/10/2326.full.pdf

Polymorphisms in DNA Repair Genes, Medical Exposure to Ionizing Radiation, and Breast Cancer Risk

Although cancer heterogeneity, even within individual tumors with different treatment responses of subcloncal cells populations, suggests the need for personalized medicine, most funding and efforts go to conventional single gene-based research and comparative-effectiveness research. Cancer arises from changes in the DNA sequence in the genomes of cancer cells. These accelerating somatic mutations dysregulate signaling pathways, including EGFR, Wnt/Notch, Hedgehog and others, with a central role in cell growth, proliferation, survival, angiogenesis and metastasis. All of these genetic alterations can now be discovered using next-generation DNA sequencing technology. This high-throughput technology can achieve two major goals: first, to complete the catalogue of driver mutations, including point mutations, rearrangements and copy-number changes, by full and targeted sequencing; and second, to explore the functional role of cancer genes and their interactions by genome-wide RNA, serial analysis of gene expression, microRNAs, protein-DNA interactions, and comprehensive analyses of transcriptomes and interactomes. This review article discusses the challenges, including costs, in completing the catalogue of driver mutations for each cancer type and understanding how cancer genomes operate as whole biological systems. Now high-quality clinical treatment and outcomes (death or survival) data from biobanks, and extensive genetics and genomics data for some common tumors, including breast, colorectal and pancreatic cancer, are available. In this article, we will describe how all these clinical and genetics data could be integrated into reverse engineering-based network modeling to approach the extremely complex genotype-phenotype map. This clinico-genome systems model, published for the first time, opens the way for the discovery of new molecular innovations, both predictive markers and therapies, towards personalized treatment of cancer. Instead of the comparative-effectiveness research or personalized medicine debate, harmonization of both can revolutionize cancer management.

Novel clinico-genome network modeling for revolutionizing genotype-phenotype-based personalized cancer care

Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFs1, IGFBP3) were evaluated. Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFs1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted.

/pdf/kin-cohort-estimates-for-familial-breast-cancer-risk-in-3xqtskmqw9.pdf

Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes

OBJECTIVES A functional polymorphism in the promoter region of the 5-hydroxytryptamine (serotonin) transporter (5-HTT) gene, termed 5-HTTLPR, alters transcription of the 5-HTT gene The short variation (S allele) produces less transcriptional efficiency of serotonin, which can partly account for psychiatric disorders Despite strong biological plausibility, the relationship between 5-HTTLPR and the risk of major depressive disorder (MDD) is unclear To elucidate the relationship, we applied meta-analysis techniques to molecular studies of 5-HTTLPR and MDD METHODS A total of 22 articles were identified from MEDLINE through March 2008, using the search keywords 'depression,' '5-HTTLPR', and 'polymorphism' The authors assessed the evidence of genotypic association using STATA Version 82 RESULTS Summary frequencies of the S allele of 5-HTTLPR among Caucasians and Asians based on the random effects model were 421% [95% confidence interval (CI) = 405-436] and 768% (95% CI = 739-797), respectively The distribution of the S allele was significantly different between Asians and Caucasians (P<0001) The SS genotype was significantly associated with an increased risk of MDD among Caucasian populations (odds ratio = 141, 95% CI = 115-172), although there was no significant association among Asians CONCLUSION Although the summary risk for developing MDD in individuals with the 'at-risk' SS genotype of 5-HTTLPR may be small, MDD is such a common disease that even a small increase in risk translates to a large number of excess MDD cases in the population Thus, 5-HTT may be a candidate MDD susceptibility gene

/pdf/association-between-major-depressive-disorder-and-a-39pck9thel.pdf

Association between major depressive disorder and a functional polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: a meta-analysis.

The BRCA2 N372H nonconservative amino acid substitution polymorphism appears to affect fetal survival in a sex-dependent manner, and the HH genotype was found to be associated with a 1.3-fold risk of breast cancer from pooling five case-control studies of Northern European women. We investigated whether the BRCA2 N372H polymorphism was associated with breast cancer in Australian women using a population-based casecontrol design. The BRCA2 372 genotype was determined in 1397 cases under the age of 60 years at diagnosis of a first primary breast cancer and in 775 populationsampled controls frequency matched for age. Casecontrol analyses and comparisons of genotype distributions were conducted using logistic regression. All of the statistical tests were two-tailed. The HH genotype was independent of age and family history of breast cancer within cases and controls, and was more common in cases (9.2% versus 6.5%). It was associated with an increased risk of breast cancer, 1.47-fold unadjusted (95% confidence interval, 1.05–2.07; P 0.02), and 1.42fold (95% confidence interval, 1.00 –2.02; P 0.05) after adjusting for measured risk factors. This effect was still evident after excluding women with any non-Caucasian ancestry or the 33 cases known to have inherited a mutation in BRCA1 or BRCA2, and would explain 3% of breast cancer. The BRCA2 N372H polymorphism appears to be associated with a modest recessively inherited risk of breast cancer in Australian women. This result is consistent with the findings for Northern European women.

The BRCA2 372 HH Genotype Is Associated with Risk of Breast Cancer in Australian Women Under Age 60 Years 1

Risks of Breast, Ovarian, and Contralateral Breast Cancer for $\textit{BRCA1}$ and $\textit{BRCA2}$ Mutation Carriers

5810 Prostate cancer (PrCa) is the commonest cancer in developed countries. It exhibits consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common PrCa susceptibilility alleles, we conducted a genome-wide association study using 1,854 PrCa cases with clinically detected prostate cancer diagnosed at

Identification of multiple novel prostate cancer susceptibility loci by a genome-wide association study

Objectives: A case-control-family study of breast cancer in women under the age of 40 was carried out in Melbourne and Sydney, Australia, from 1992 to 1995 to determine the risk factors for these women. Subjects included 467 incident cases identified by state cancer registries and 408 population-based controls. Methods: All participants completed a structured risk-factor questionnaire and family pedigree during an in-person interview. Where possible, cancers in first- and second-degree relatives were verified. Results: Multiple logistic regression analysis showed that the strongest risk factor for breast cancer was a family history of the disease - having at least one affected first-degree relative trebled the risk (relative risk [RR] = 3.3, 95 percent confidence interval [CI] = 1.9-5.8). Risk increased with height by three percent (standard error [SE] of one percent) per cm, and after adjusting for height, there was evidence for a decreased risk in women weighing 73 kg or more. There was an increased risk of breast cancer after the first full-term birth (RR = 1.8, CI = 1.0-3.5) but this risk fell by 30 percent (SE = 11 percent) with each subsequent livebirth. Conclusions: The effects of other reproductive factors and oral contraceptive use, although not nominally significant, were in accord with published findings from similar studies in young women. This study of Australian women has indicated that some risk factors for breast cancer in women under age 40 differ from those reported for older women either in direction (e.g., weight) or relative importance (e.g., family history). Cancer Causes and Control 1998, 9, 189-198

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The BRCA2 372 HH Genotype Is Associated with Risk of Breast Cancer in Australian Women Under Age 60 Years 1

Risks of Breast, Ovarian, and Contralateral Breast Cancer for $\textit{BRCA1}$ and $\textit{BRCA2}$ Mutation Carriers

Identification of multiple novel prostate cancer susceptibility loci by a genome-wide association study

under the age of 40