- A high score based on the expression of 23 genes involved in repairing DNA damage after platinum-based chemotherapy for ovarian cancer was associated with improved survival.
- Note that the gene score outperformed clinical factors associated with ovarian cancer outcome and was the only baseline factor that had a significant association with overall survival.
Showing posts with label genetics. Show all posts
Showing posts with label genetics. Show all posts
Friday, May 25, 2012
Full-Exon Pyrosequencing Screening of BRCA Germline Mutations in Mexican Women with Inherited Breast and Ovarian Cancer
Full-Exon Pyrosequencing Screening of BRCA Germline Mutations in Mexican Women with Inherited Breast and Ovarian Cancer:
Hereditary breast cancer comprises 10% of all breast cancers. The most prevalent genes causing this pathology are BRCA1 and BRCA2 (breast cancer early onset 1 and 2), which also predispose to other cancers. Despite the outstanding relevance of genetic screening of BRCA deleterious variants in patients with a history of familial cancer, this practice is not common in Latin American public institutions. In this work we assessed mutations in the entire exonic and splice-site regions of BRCA in 39 patients with breast and ovarian cancer and with familial history of breast cancer or with clinical features suggestive for BRCA mutations by massive parallel pyrosequencing. First we evaluated the method with controls and found 41–485 reads per sequence in BRCA pathogenic mutations. Negative controls did not show deleterious variants, confirming the suitability of the approach. In patients diagnosed with cancer we found 4 novel deleterious mutations (c.2805_2808delAGAT and c.3124_3133delAGCAATATTA in BRCA1; c.2639_2640delTG and c.5114_5117delTAAA in BRCA2). The prevalence of BRCA mutations in these patients was 10.2%. Moreover, we discovered 16 variants with unknown clinical significance (11 in exons and 5 in introns); 4 were predicted as possibly pathogenic by in silico analyses, and 3 have not been described previously. This study illustrates how massive pyrosequencing technology can be applied to screen for BRCA mutations in the whole exonic and splice regions in patients with suspected BRCA-related cancers. This is the first effort to analyse the mutational status of BRCA genes on a Mexican-mestizo population by means of pyrosequencing.
add your opinions
genetics
,
latin america
,
latino women
,
mexican women
,
Mexico
Thursday, May 17, 2012
paywalled: Long-term results of screening with magnetic resonance imaging in women with BRCA mutations : British Journal of Cancer
Long-term results of screening with magnetic resonance imaging in women with BRCA mutations : British Journal of Cancer
Background:
The
addition of breast magnetic resonance imaging (MRI) to screening
mammography for women with BRCA mutations significantly increases
sensitivity, but there is little data on clinical outcomes. We report
screening performance, cancer stage, distant recurrence rate, and breast
cancer-specific mortality in our screening study.
Methods:
From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2
mutation, of whom 380 had no previous cancer history, were enrolled in a
prospective screening trial that included annual MRI and mammography.
Results:
In
1847 screening rounds, 57 cancers were identified (53 screen-detected, 1
interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9%
from 2003 to 2009 (P<0.0001), respectively. The relative
sensitivities of MRI and mammography did not differ by mutation, age, or
invasive vs non-invasive disease. Of the incident cancers, 97%
were Stage 0 or 1. Of 28 previously unaffected women diagnosed with
invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%).
Three patients died of other causes. None of the 24 survivors has had a
distant recurrence at a median follow-up of 8.4 years since diagnosis.
Conclusion:
Magnetic resonance imaging surveillance of women with BRCA1/2
mutations will detect the majority of breast cancers at a very early
stage. The absence of distant recurrences of incident cancers to date is
encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.
add your opinions
BRCA
,
breast imaging
,
genetics
,
MRI
Wednesday, May 09, 2012
paywalled: The Predictive Capacity of Personal Genome Sequencing - Science Translational Medicine
[Research Articles] The Predictive Capacity of Personal Genome Sequencing:
New DNA sequencing methods will soon make it possible to identify all germline variants in any individual at a reasonable cost. However, the ability of whole-genome sequencing to predict predisposition to common diseases in the general population is unknown. To estimate this predictive capacity, we use the concept of a "genometype." A specific genometype represents the genomes in the population conferring a specific level of genetic risk for a specified disease. Using this concept, we estimated the maximum capacity of whole-genome sequencing to identify individuals at clinically significant risk for 24 different diseases.
add your opinions
dna
,
genetic testing
,
genetics
,
genome
,
predisposition
,
whole genome testing
(in research - genome) Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma
Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma
Background
Small sample sizes used in previous studies result in a lack of overlap between the reported gene signatures for prediction of chemotherapy response. Although morphologic features, especially tumor nuclear morphology, are important for cancer grading, little research has been reported on quantitatively correlating cellular morphology with chemotherapy response, especially in a large data set. In this study, we have used a large population of patients to identify molecular and morphologic signatures associated with chemotherapy response in serous ovarian carcinoma.
add your opinions
genetics
,
genome
,
serous ovarian cancer
May 7th: The connection between genes and colon cancer (Lynch Syndrome/FAP) - MD Anderson Cancer Center - audio/ iTunes
The connection between genes and colon cancer - MD Anderson Cancer Center
Cancer Newsline -
05/07/2012
About 20% of colon cancer cases are related to a strong family history of colon cancer. Eduardo Vilar-Sanchez, M.D., Ph.D., Assistant Professor in the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center, focuses his discussion on the main types of genetic colon cancers including hereditary nonpolyposis colorectal cancer syndrome or HNPCC (also called Lynch syndrome) and familial adenomatous polyposis (FAP).
- Listen to The connection between genes and colon cancer
- Download The onnection between genes and colon cancer on iTunes
add your opinions
colorectal cancer genetics
,
FAP
,
genetics
,
Lynch Syndrome
Monday, May 07, 2012
Sunday, May 06, 2012
Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)
Epigenetic modification and cancer: mark or stamp?
Abstract
Hypotheses are built upon data, but
data require hypotheses before they can be understood. The development
of the ‘two-hit’
hypothesis of carcinogenesis was a key event in
cancer genetics because it provided a testable model of how tumours
develop.
In this commentary on ‘Promoter hypermethylation
patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role
of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............
Introduction
In hereditary tumours, the first hit
occurs in the germ line, whereas in non-hereditary tumours, the first
hit occurs in the
cell from which the tumour arises. The second
hits are always somatic, and can inactivate the second allele in various
different
ways. The development of the ‘two-hit’
hypothesis of carcinogenesis was a key event in cancer genetics because
it provided
a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of
genomic DNA.............
continue to read full paper
add your opinions
BRCA
,
epigenetics
,
fallopian tube
,
genetics
,
genome
,
germline mutations
,
hereditary
,
mutations
Saturday, May 05, 2012
paywalled: US firm corners exclusive license for RAD51C cancer gene : The Lancet Oncology (breast/ovarian mutation)
US firm corners exclusive license for RAD51C cancer gene : The Lancet Oncology
"Already facing a legal challenge to its BRCA1 and BRCA2 patents,
Myriad Genetics (Salt Lake City, UT, USA) has secured an exclusive
licence for another breast and ovarian cancer-associated gene, RAD51C ,
under agreement with the German Consortium for Hereditary Breast and
Ovarian Cancers, which will share exclusivity in Germany. RAD51C will be used to test patients' hereditary breast and ovarian cancer risks.
“I think it is unfortunate for both the clinical and research communities”, Jim Evans (University"
Editorial: Serrated Polyposis: The Last (or Only the Latest - Frontier of Familial Polyposis (Lynch Syndrome/familial/pre-malignant adenomas)
Wiki: Sessile serrated adenoma
In gastroenterology, a sessile serrated adenoma (abbreviated SSA), also known as sessile serrated polyp (abbreviated SSP), is a premalignant flat (or sessile) lesions of the colon, predominantly seen in the cecum and ascending colon.
Editorial: Serrated Polyposis: The Last (or Only the Latest|[quest]|) Frontier of Familial Polyposis|[quest]| : The American Journal of Gastroenterology
The American Journal of Gastroenterology 107, 779-781 (May 2012) | doi:10.1038/ajg.2012.62
Editorial: Serrated Polyposis: The Last (or Only the Latest?) Frontier of Familial Polyposis?
Stephen J Lanspa, Dennis J Ahnen and Henry T Lynch
Abstract
Serrated polyps are thought to be precursors of ~15%
of colorectal cancers and clinical criteria for a serrated polyposis
(SP) syndrome have been proposed. In this issue of American Journal of
Gastroenterology, Win et al. report that family members of individuals
who meet the clinical criteria for SP are at increased risk for
colorectal and possibly pancreatic cancer. The important data presented
by Win et al. strongly support the concept that familial SP exists and
help define the patterns of risk in this syndrome. The paper also
illustrates the difficulties of trying to define a genetic syndrome on
the basis of largely retrospective clinical data and highlights the
importance of efforts to define the genetic basis of familial SP and to
study these families in a systematic, prospective manner.
add your opinions
adenomas
,
cecum
,
colon
,
colorectal
,
familial syndrome
,
genetics
,
Lynch Syndrome
,
pancreatic
,
premalignant
,
serrated polyps
paywalled: Dosage Effect of BRCA1 and BRCA 2 Mutated Allelic Transcript (French Canadian)
Dosage Effect of BRCA1/2-Mutated Allelic Transcript:
We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation.
We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation.
Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript.
add your opinions
8765delAG
,
BRCA 1
,
BRCA 2
,
genetic mutations
,
genetics
Wednesday, May 02, 2012
Family history: Still relevant in the genomics era - Cleveland Clinic
Family history: Still relevant in the genomics era
Key points
- The family history is an underused tool for predicting the risk of disease and for personalizing preventive care.
- Barriers to the appropriate collection and use of the family history include concerns over the reliability of patient reporting, a lack of time and reimbursement, and provider knowledge gaps.
- Use of family history to inform genetic testing for hereditary cancer syndromes has been shown to improve outcomes and may reduce overall health care costs.
- Future solutions need to focus on creating time-effective ways to collect and analyze the family history, and on developing innovative methods of educating medical providers at all levels of training as to how to apply the family history in clinical practice.
add your opinions
family history
,
genetics
Tuesday, May 01, 2012
NIH grants $10.5 Million for Genome Explorations -The Burrill Report
NIH grants $10.5 Million for Genome Explorations -The Burrill Report:
The National Human Genome Research Institute, part of the National Institutes of Health, is awarding $10.5 million in ten grants to help researchers identify millions of genomic elements that play a role in determining what genes are expressed and at what levels in different cells. The multi-year grants are part of the Encyclopedia of DNA Elements project, or ENCODE, set up to provide scientists with a comprehensive catalog of functional genomic elements. The project's goal is to help explain the role that the genome plays in health and disease.
add your opinions
genetics
,
genome grants
,
grants
,
NIH
Monday, April 30, 2012
paywalled: Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery (Lynch Syndrome, breast/ovarian BRCA 2....)
Blogger's Note: while full access is by subscription only, key words indicate 'high risk' categories not limited to Lynch Syndrome, BRCA 2; BRCA 2 - blogger's assumption based on genetics in absence of full text acccess)
Individuals at high-risk for pancreatic cancer development: Management options and the role of surgery
Abstract
Pancreatic cancer (PC) is a highly lethal disease. Despite advances regarding the safety and long-term results of pancreatectomies, early diagnosis remains the only hope for cure. This necessitates the implementation of an intensive screening program (based mainly on modern imaging), which – given the incidence of PC – is not cost effective for the general population. However, this screening program is recommended for individuals at high-risk for PC development.Indications for screening include the following three clinical settings: hereditary cancer predisposition syndromes associated with PC, hereditary pancreatitis and familial pancreatic cancer syndrome. The aim of this strategy is to identify pre-invasive (precursor) lesions, which are curable. Surgery is recommended in the presence of recognizable lesion on imaging lesions. Partial (anatomic) pancreatectomy – depending on the location of the suspicious lesion – is the most widely accepted type of surgical intervention in this setting; occasionally, however, total pancreatectomy may be required, in carefully selected patients. Despite that experience still remains limited, there is evidence that this aggressive strategy allows early detection of neoplastic lesions, thereby improving the effectiveness of surgery and prognosis.
Keywords: Pancreas, Surgery, Cancer, PanIN, MCN, IPMN, Pancreatectomy, Total pancreatectomy, Screening
Abbreviations: PanIN, pancreatic intraepithelial neoplasia, IPMN, intraductal papillary mucinous neoplasm, MCN, mucinous cystic neoplasm, PJS, Peutz–Jeghers syndrome, FAMMM syndrome, familial atypical multiple mole melanoma syndrome, HNPCC, hereditary non-polyposis colon cancer (Lynch syndrome), HOBC, hereditary ovarian and breast cancer, VHL, von Hippel–Lindau, PD, pancreatoduodenectomy
add your opinions
BRCA 2
,
genetics
,
hereditary breast ovarian
,
high risk
,
Lynch Syndrome
,
pancreas
,
pancreatectomy
,
pancreatic cancer
,
risk reduction
Thursday, April 26, 2012
paywalled: Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer.
Breast Cancer Res Treat. 2012 Apr 18;
Abstract
The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case-control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case-control studies to deliver robust genetic evidence of disease association.
add your opinions
breast cancer
,
breast cancer genes
,
genetics
,
variants
Friday, April 20, 2012
Monday, April 16, 2012
Saturday, April 14, 2012
Medpage: Medical News: DNA Repair Genes May Predict Ovarian Cancer Survival
Blogger's Note: the original paper and editorial were recently posted, however, the Medpage (Medscape) article is easier to read (eg. plain english)
DNA Repair Genes May Predict Ovarian Cancer Survival - in Oncology/Hematology, Ovarian Cancer from MedPage Today
"A high score based on the expression of 23 genes involved in repairing DNA damage after platinum-based chemotherapy for ovarian cancer was associated with a 5-year survival of 40% versus 17% for women who had a low score, investigators reported......"
Action Points
add your opinions
dna
,
genetics
,
genome
,
ovarian cancer survival
open access: Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome
ScienceDirect.com - Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome
"....While endometrial cancer diagnosed under the age of 50 is not included in the Revised Bethesda Guideline, evidence suggests that these individuals should be evaluated for Lynch syndrome (Resnick et al., 2009). The patient presented was diagnosed with endometrial cancer at the age of 41 and genetic testing revealed triple heterozygosity for BRCA2, MLH1 and MSH6 mutations."
Introduction
Lynch
syndrome, also called hereditary non-polyposis colorectal cancer
(HNPCC), is an autosomal dominant cancer susceptibility syndrome caused
by germline mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and less frequently MSH6 and PMS2.
MMR mutation carriers are predisposed primarily to colorectal cancer
and endometrial cancer, with an increased frequency of stomach, ovary,
pancreas, upper urinary tract, brain, small bowel, and skin consistently
reported. This hereditary syndrome accounts for approximately 2–3% of
colorectal cancers and 1–4% of endometrial cancers in the United States (Lynch and de la Chapelle, 2003).
Depending on the MMR gene involved, women with Lynch syndrome can have
up to an 80% lifetime risk of developing colorectal cancer, and a 20–60%
risk of endometrial cancer.
Germline mutations in BRCA1 or BRCA2
(BRCA1/2) cause hereditary breast ovarian cancer syndrome. Female
carriers of BRCA1/2 mutations have excessive risks for both breast and
ovarian cancer, with lifetime breast cancer estimates ranging from 45%
to 84%, and lifetime ovarian cancer estimates ranging from 11% to 62%,
depending upon the population studied. BRCA1/2 kindreds are also noted
to have an increased frequency of prostate cancer, and in BRCA2 kindreds, increased frequencies of pancreatic cancer and melanoma are observed. The frequency of BRCA1 or BRCA2 mutations in the general population is estimated to be 1 in 300 to 1 in 800, respectively (King et al., 2003).
Highlights
►
Endometrial cancer with BRCA2 mutation and double heterozygosity for
Lynch syndrome.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.
add your opinions
bethesda guidelines
,
BRCA
,
brca1 brca1
,
genetics
,
Lynch Syndrome
,
MLH1
,
MSH6
,
mutations
,
triple heterozygosity
Sunday, April 01, 2012
press release: Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene (Lynch syndrome)
Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene
"This study demonstrates the importance of the analyzing the PMS2 gene to fully comprehend a patient's Lynch syndrome status."
add your opinions
genetics
,
Lynch Syndrome
,
PMS2
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