abstract: Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

"Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers.
The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations.
The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers.
The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p<10(-4)). In contrast, the cumulative risk of cancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives."

A whisper-game perspective on the family communication of DNA-test results: a retrospective study on the communication process of BRCA1/2-test results

"...Unclassified-variants were most frequently misinterpreted by probands and relatives, and had the largest differences between probands' and relatives' perceptions...."

Germline Genetic Variation, Cancer Outcome, and Pharmacogenetics — JCO

Abstract

"Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome (Lynch Syndrome). ...."cont'd

New Whitehead Fellow on the Hunt for Rare Genetic Mutations

New Whitehead Fellow on the Hunt for Rare Genetic Mutations

"As Whitehead Institute’s newest Fellow, Yaniv Erlich comes to Cambridge in search of needles in very large haystacks.In Erlich’s case, the needles are rare genetic variants or mutations occurring in individual human genomes. His quest is born of the growing realization that large-scale genome sequencing projects—genome-wide association studies (GWAS)—are failing to pinpoint genetic causes of common diseases. Indeed, mounting evidence suggests that the common genetic mutations that GWASs have surfaced reveal little about disease manifestation and inheritance risk.
It now appears that rare variants are behind many diseases, prompting the development of the so-called common disease-rare variant hypothesis...."cont'd

full free access: Preparing for a Consumer-Driven Genomic Age Health Policy and Reform

"Advances in genomic technologies permit the simultaneous analysis of millions of variants across the genome and may soon allow for meaningful estimation of one’s risks of developing cancer, diabetes, and other common diseases. These advances are converging with the movement toward consumer-driven health care and patient empowerment. Whereas in the past, medical testing was firmly under the control of medical practitioners, genomic information is now increasingly available outside traditional medical settings. Patients are no longer subordinate, passive recipients of physician-initiated genetic testing; rather, patients can instigate their own testing and often know more than their clinicians about particular genetic topics. Indeed, health care providers are increasingly bypassed altogether, as patients embrace direct-to-consumer (DTC) genetic tests and turn to social networks for help in interpreting their results. In the future, a primary role of health care professionals may be to interpret patients’ DTC genetic test results and advise them about appropriate follow-up. How can we maximize the benefits of these new developments and minimize the harms? How can we encourage patients’ involvement and autonomy yet establish appropriate safeguards while avoiding inappropriate paternalism? How do we promote the understanding that interpretations of genomic information may evolve as research unravels the meaning of gene–gene and gene–environment interactions and the roles of noncoding DNA sequences, copy-number variants, epigenetic mechanisms, and behavioral factors in health and disease?..."cont'd

Expert Opinion on Medical Diagnostics - KRAS mutations - Summary

What the reader will gain: KRAS mutations in mCRC and NSCLC primary tumors predict resistance to EGFR-targeted therapy. In pancreatic cancer, KRAS may prove useful as a diagnostic biomarker to screen for early neoplasia. Furthermore, quantitative KRAS mutation analysis could have the potential to distinguish pancreatic cancer from other conditions such as chronic pancreatitis.

With respect to ovarian and endometrial cancer, further studies should focus on determining reliable biomarkers for predicting response to EGFR-targeted therapy. Besides EGFR inhibition, KRAS may also serve as a diagnostic and predictive biomarker for evolving therapies directed against mutant RAS proteins.

Take home message: KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.

See also blog post:

Wednesday, July 21, 2010

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)

Low-Penetrance Susceptibility Variants in Familial Colorectal Cancer — Cancer Epidemiology, Biomarkers & Prevention

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA 1 by Structural and Functional Assays

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Authors' Affiliations: Department of Biochemistry, School of Systems Molecular Medicine, University of Alberta, Edmonton, Alberta, Canada; National Institute of Environmental Health Sciences, Durham, North Carolina; Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Molecular Biology Program, Institute of Biophysics Carlos Chagas Fo., Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer....... Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.

The BRCA1 c.5434C→G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements -- Gaildrat et al. 47 (6): 398 -- Journal of Medical Genetics

Blogger's Note: in plain english - many patients who have undergone genetic testing show test results of 'unknown variants' or variants of unknown clinical significance but negative for known mutations ie; BRCA 1/2; MSH2/6; MLH1; PMS2.
Some of these unclassified variants may or may not be related to cancer. With recent research, databases are now showing UV (unclassified variants) as true mutations.
This article is one of many which shows the work being done to explain and find the significance of these variants. Many patients undergoing genetic testing will test negative for the commonly known mutations, but this is not the'end of the story', so to speak.


Conclusion These data, together with segregation data, argue for the classification of BRCA1 c.5434C→G as a pathogenic splicing mutation. These results also suggest that UVs (unclassified variants)in highly conserved nucleotide sequences of short exons may be good candidates for detecting functionally relevant splicing regulatory elements.