abstract: Familial Cancer - Mutation deep within an intron of MSH2 causes Lynch syndrome

"...thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation."

full free access: Poly(ADP-Ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic - A Cancer Journal for Clinicians - Wiley Online Library

see also:   
Table 1. DNA Repair Pathways
(Lynch Syndrome, BRCA 1/2, FANC, ATM, MYH ;  
Table 2. PARP Inhibitor Clinical Trials; Other Potential Synthetic Lethal Strategies for PARP Inhibitors.....

Conclusions: 
"The synthetic lethal targeting of DNA repair pathways, as exemplified by PARP inhibitors, in cancers bearing HR DNA repair defects is showing considerable potential for delivering selective tumor cell kill while sparing normal cells, and offers a scientifically rational and potentially broad clinical application in oncology.64 Several challenges related to the development of these inhibitors remain, including the identification of robust predictive biomarkers of HR deficiency in cancers. The dissection of the underlying mechanisms of PARP inhibitor resistance and establishment of optimal drug combinations and strategies for chemoprophylaxis with these therapies remain high priorities. It is important to be aware that different PARP inhibitors may have varying potencies on individual members of the PARP superfamily and also affect other targets, resulting in distinct toxicity and efficacy profiles. In the future, it is envisioned that this tumor-specific synthetic lethal strategy with PARP inhibitors may potentially be utilized against cancers with similar molecular defects but diverse anatomical origins.118 Such a paradigm shift in drug discovery may crucially bring us closer to our ultimate goal of personalized medicine."

Genetics University of Utah - Tour of the Basics - Understanding Genes, Chromsomes

What is DNA?
What is a Gene?
What is a Protein?
What is Hereditary?
What is a Trait?

A Third-Generation Map of Human Genetic Variation

An international consortium has published the largest survey of human genetic variation thus far: a third-generation map that includes data from 11 global populations. The accomplishment will help in the ongoing search for genetic variants associated with complex diseases.

Any 2 people are more than 99% the same at the genetic level. The small variations between people can help explain differences in susceptibility to disease, response to drugs or reaction to environmental factors.
Stretches of DNA sequence tend to be inherited together. Thus, sets of small genetic variations called single nucleotide polymorphisms (SNPs) tend to be grouped. These clusters are called haplotypes. The map of human genetic variation is called a haplotype map, or HapMap.
Previous versions of the HapMap were built on the analysis of DNA collected from 270 volunteers from 4 geographically diverse populations. The first version contained approximately 1 million SNPs. The second-generation map brought that total to more than 3.1 million SNPs.
Over the last few years, researchers conducting genome-wide association studies have relied on data from the HapMap to discover hundreds of common genetic variants associated with complex human diseases, such as cardiovascular disease, diabetes, cancer and many other health conditions. Funding to create the third-generation HapMap was provided by NIH’s National Human Genome Research Institute (NHGRI), National Institute on Deafness and Other Communication Disorders (NIDCD) and the Wellcome Trust.
For the latest version, researchers analyzed about 1.6 million SNPs in a much broader range of samples from around the world. As reported in the September 2, 2010, issue of Nature, the HapMap now includes data from an additional 7 global populations, bringing the total number of volunteers to almost 1,200.
The consortium also carefully sequenced 10 regions totaling about 1 million base pairs in 692 samples. The scientists found that 77% of the SNPs they detected were new. This result shows that many more variants remain to be found, especially rare variants. In addition, the scientists added more than 800 copy-number variants to the resource. These reflect differences in the number of copies of specific DNA regions people harbor.

"The generated HapMap provides an important foundation for studies aiming to find genetic variation related to human diseases," says NHGRI Director Dr. Eric D. Green. "It is now routinely used by researchers as a valuable reference tool in our quest to use genomics for improving human health."

Many of the HapMap researchers are also part of the 1000 Genomes Project, an international public-private consortium launched in 2008 to build an even more detailed map of human genetic variation. The scientists are using next-generation DNA sequencing technologies to build a public database with information from the complete genomes of 2,500 people from 27 populations around the world, many of which were studied in the HapMap project. Researchers will be able to use this data to expand their studies of how common and rarer genetic variations contribute to illness.

Related Links:

• Second-Generation Map of Human Genetic Variation:
  http://www.nih.gov/researchmatters/october2007/10292007variation.htm
• International HapMap Project:

DNA discovery opens new door to develop tools, therapies for hereditary cancers (in research)

"....Errors in DNA can arise from many types of damage including external harm, such as UV radiation or carcinogens, as well as by intrinsic cellular processes such as DNA replication. Failure to correct these errors leads to mutations, which results in cancer or a number of severe genetic disorders."

“The reason why it can lead to cancer is because if you don’t have mismatch repair proteins that correct these errors, you’re going to accumulate mutations,” said Guarné. “People with defective mismatch repair genes develop cancers at very early ages. You would see a family that in their 30s has colorectal cancer and in their 40s they have it again. There’s no way you can prevent that – you can’t correct your DNA. As you grow older, you’re going to accumulate mutations.”

Stem cell researchers uncover previously unknown patterns in DNA methylation

"The findings could have implications in fighting cancer because DNA methylation patterns go awry in cancer, often causing tumor suppressor genes to switch off. The more scientists know about the cellular mechanisms that lay down the correct DNA methylation patterns, the more that process can be manipulated. In the future, this type of research may lead to techniques that result in the ability to control the patterns that go awry and lead to cancer, thus preventing a malignancy"

Hormone therapy, DNA methylation and colon cancer-- Carcinogenesis

Genetic/Familial high-risk assessment: breast and ... [J Natl Compr Canc Netw. 2010] - PubMed result

Abstract

Overview
All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair,(1,2) but not all of these mutations are inherited from a parent. For example, sporadic mutations can occur in somatic/tumor cells only, and de novo mutations can occur for the first time in a germ cell (i.e., egg or sperm) or in the fertilized egg itself during early embryogenesis. However, family studies have long documented an increased risk for several forms of cancer among first-degree (i.e., parents, siblings, and children) and second-degree relatives (i.e., grandparents, aunts or uncles, grandchildren, and nieces or nephews) of affected individuals. These individuals may have an increased susceptibility to cancer as the result of 1 or more gene mutations present in parental germline cells; cancers developing in these individuals may be classified as hereditary or familial cancers. Hereditary cancers are often characterized by mutations associated with a high probability of cancer development (i.e., a high penetrance genotype), vertical transmission through either mother or father, and an association with other types of tumors.(3,4) They often have an early age of onset and exhibit an autosomal dominant inheritance pattern (i.e., occur when the individual has a mutation in only 1 copy of a gene). Familial cancers share only some features of hereditary cancers. For example, although familial breast cancers occur in a given family more frequently than in the general population, they generally do not exhibit the inheritance patterns or onset age consistent.

Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

Note: in research/technical

full access: DNA Methylation Profiles of Ovarian Epithelial Carcinoma Tumors and Cell Lines

Table 1

Histology and clinical characteristics of primary ovarian tumors. (serous, endometrioid, clear cell - CA125 levels, menopausal status,patient age)

Background

Epithelial ovarian carcinoma is a significant cause of cancer mortality in women worldwide and in the United States. Epithelial ovarian cancer comprises several histological subtypes, each with distinct clinical and molecular characteristics. The natural history of this heterogeneous disease, including the cell types of origin, is poorly understood.

Mismatch repair status and outcomes after adjuvant therapy in patients with surgically staged endometrial cancer (Lynch Syndrome mutations)

OBJECTIVES: "To determine whether DNA mismatch repair (MMR) modifies the response to chemotherapy or radiotherapy in patients with endometrial cancer...... METHODS: Immunohistochemistry (IHC) for the DNA MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed on a tissue microarray of specimens of primary endometrial cancer."

(abstract) Aberrant DNA methylation in contrast with mutations. 2009; Cancer Science

Note: technical/short abstract