Norway Launches National Cancer Genomic Medicine Effort | GenomeWeb

Blogger's Note: requires registration to view (free)

NEW YORK (GenomeWeb News) – "Norway has kicked off a national collaborative effort to use deep sequencing to discover and use genetic mutations for treating cancer patients and to create a program for using genomic medicine in the clinic...."

Hereditary ovarian cancer: Beyond the usual suspects - abstract (Fanconi anemia–BRCA,PARP, RAD51C, RAD51D,BRIP1

Blogger's Note: see post Myriad Genetics  rights/RAD51C

.....With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes........ In addition, identifying inherited mutations in a variety of FA–BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors."

---

Highlights

► Newly identified hereditary ovarian cancer genes include RAD51C, RAD51D, and BRIP1.
► Many genes in the Fanconi anemia–BRCA pathway may increase risk of ovarian cancer.
► New genomic technologies make comprehensive genetic assessment feasible.

abstract: Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer

BACKGROUND:

Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.

CONCLUSIONS:

BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

Abstract

The genetic basis for gastric and pancreatic cancer is largely undetermined.
These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes.
Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer.
To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143–70%) were Ashkenazi Jews, and 10% (n = 16)—of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96–67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984_3987dupGTCA and c.3959_3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations.
We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients"

Factors Associated with Altered Long-Term Well-Being After Prophylactic Salpingo-Oophorectomy Among Women at Increased Hereditary Risk for Breast and Ovarian Cancer

Blogger's note: full view may require $$$ (subscription)

link to abstract

free full access: Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations

Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations

• Full Text
• PDF

Article Outline

• Positive BRCA1 or BRCA2
• Negative BRCA1 and BRCA2
• Variant of Uncertain Clinical Significance
• Case No. 1: BRCA1 VUS
  • Clinical Discussion Points
• Case No. 2: BRCA2 VUS
• Case No. 3: BRCA2 VUS Favoring Polymorphism
• Clinical Discussion Points (Cases No. 2 and 3)
• Clinical Geneticists' Opinions
• Cancer Geneticists' Opinions
• Clinical Geneticists' Opinions
• Discussion
• References
• Copyright

abstract: Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples

The predicted truncation from a (ovarian) cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex

Abstract

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS...."(technical)

Cancer Genome Atlas (press release July 2011) TCGA Completes Ovarian Cancer (serous) Analysis - TCGA plus link to video discussion

To view a video of Dr. Spellman discussing TCGA and the ovarian cancer findings, please go to http://www.youtube.com/watch?v=TK_CIGEUHxU

Detailed 'genetic landscape' of ovarian cancer revealed : Cancer Research UK

Note: nice 'plain english language' article

medical news: Sequence of ovarian genome identifies predominant gene mutations, points to possible treatment

"....While high-grade serous ovarian adenocarcinoma is conventionally considered as one type of cancer having uniform features, "we could divide the tumors into four different groups based on gene expression patterns," said Creighton. "They look like four different cancers."
"We were able to define a set of genes that were associated with worse outcomes versus better outcomes in patients," he said. They applied this gene signature to other sets of data collected about ovarian cancer and found that the profile predicted worse or better outcome there as well.
"These data are all public (blogger's note - refers to the Cancer Genome Atlas)," said Creighton. "They are meant for people to use to find specific genes for research. They could influence a lot of future studies."...cont'd

The Cancer Genome Atlas completes detailed ovarian cancer analysis - GenOmics

also: A more detailed press release on the study will be available from the National Institutes of Health at http://nih.gov/news/.

extract: Cancer Risk Assessment in Lynch Syndrome, June 8, 2011 — JAMA

News - Penn State Biochemistry and Molecular Biology Colorectal Cancer month/Lynch Syndrome excerpt

"Lynch syndrome, previously referred to as hereditary non-polyposis colorectal cancer or HNPCC, represents the most common hereditary cause of colorectal cancer.
Approximately 1 in 400 to 1 in 500 individuals in the general population are estimated to have Lynch syndrome.

Knowledge, as they say, in this condition, is power. Not only should individuals with Lynch syndrome start their colonoscopies earlier (at 20-25 years of age) and have them more frequently (every 1-2 years), they should also be screened for stomach and small intestine cancer, urinary tract cancers involving the kidneys and ureters, and the hepatobiliary tract, including the gallbladder, bile duct, pancreas and liver.

Further, women with Lynch syndrome should be aware of the increased risk for both endometrial and ovarian cancer and offered the option of prophylactic surgery following childbearing."

March 2011: Hereditary Cancer in Clinical Practice | Full text | Lynch Syndrome - is breast cancer a feature?

Background

The debate on whether or not breast cancer is in the tumor spectrum for Lynch syndrome produces a conundrum for healthcare providers.

The classic tumor spectrum for Lynch Syndrome (LS) includes colon, endometrial, ovarian, stomach, small intestine, hepatobiliary, urinary tract and brain/central nervous system cancers. Muir-Torre Syndrome (MTS) is a variant of LS that is associated with additional skin lesions including sebaceous gland tumors and keratoacanthomas. MTS was observed in 28% of LS families when assessing for MTS skin lesions [1]. It has also been reported that 10-14% of individuals with MTS present initially with breast cancer [2,3]. An extensive study published in 2002 excluded breast cancer as part of the tumor spectrum associated with LS [4].

However, more recently it was reported that DNA mismatch repair (MMR) gene deficiencies were identified in 51% of breast cancers arising in MMR mutation carriers [5]. Another study reported a male with an MLH1 mutation who had both colon and breast cancer. The breast cancer exhibited somatic reduction to homozygosity for the MLH1 mutation [6].

Here we report two unrelated families in which the proband has a germline MMR gene mutation and bilateral breast cancer, and one family in which the proband had ovarian and renal cancer and her daughter, maternal aunt and cousin had breast cancer at age 47, 59, and 48 respectively.

This raises the question are these breast cancers associated with the MMR mutations or a breast cancer susceptibility gene and what testing should be offered?

Conclusion

Our findings indicate that breast cancer is part of the spectrum of tumors in LS families in which the breast cancer segregates with the other LS associated tumors.

Additional hereditary breast cancer gene testing may not be warranted in these circumstances. A future research goal is to perform IHC on the breast tumors from these families to determine if they show loss of expression of the MMR gene that is known to be altered.

....cont'd (full free access)

Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer.

PURPOSE: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.
METHODS: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.
RESULTS: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.
CONCLUSION: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

Atlas of Genetics and Cytogenetics in Oncology and Haematology - Ovarian tumours : an overview