open access: Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian Cancers — NEJM (germ cell, sex cord-stromal, leydig, granulosa...

"Sex cord–stromal tumors and germ-cell tumors account for less than 10% of ovarian cancers.1 Unlike epithelial ovarian cancers, both sex cord–stromal tumors and germ-cell tumors can also occur in the testicle; testicular germ-cell tumors are the most common cancer in boys and men of European descent between the ages of 15 and 34 years.2,3 Other than a pathognomonic somatic mutation in FOXL2 in adult granulosa-cell tumors,4-6 little is known about the pathogenesis of ovarian sex cord–stromal tumors and germ-cell tumors. Recently, germline mutations in the microRNA processing gene DICER1 have been reported in probands with pleuropulmonary blastoma or the related familial tumor dysplasia syndrome, known as pleuropulmonary blastoma–family tumor and dysplasia syndrome (Online Mendelian Inheritance in Man [OMIM] number, 601200), which includes cystic nephroma, ovarian sex cord–stromal tumor (especially Sertoli–Leydig cell tumor), and multinodular goiter.7......."

open access: Molecular Cancer | Role of Bcl-3 in solid tumors

"In this regard, it is interesting that, in addition to the known deregulation in leukemias and lymphomas, genome-wide expression studies have shown that Bcl-3 is overexpressed in breast cancer, glioblastoma tumors, ovarian cancer and, intriguingly, teratomas and embryonal> carcinomas (additional file 2). Although not validated, these results support the potential importance of this oncogene in a variety of tumors."

Role of Bcl-3 in solid tumors

Vilma Maldonado and Jorge Melendez-Zajgla

Molecular Cancer 2011, 10:152 doi:10.1186/1476-4598-10-152
Published: 23 December 2011

Abstract (provisional)

Bcl-3 is an established oncogene in hematologic malignancies, such as B-cell chronic lymphocytic leukemias. Nevertheless, recent research has shown that it also participates in progression of diverse solid tumors. The present review summarizes the current knowledge of Bcl3 role in solid tumors progression, including some new insights in its possible molecular mechanisms of action

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

open access: Whole Genome Sequences of a Male and Female Supercentenarian, Ages Greater than 114 Years | Frontiers in Genetics of Aging

Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

Conclusion:

Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.

abstract: Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study : The Lancet Oncology (with/without brca mutation/s)

The Lancet Oncology, Early Online Publication, 22 August 2011

doi:10.1016/S1470-2045(11)70214-5Cite or Link Using DOI

Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study

 "...

Findings

91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22—64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14—38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%])...."

abstract: Secondary Somatic Mutations Restoring BRCA1/2 Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas

Conclusion: Secondary somatic mutations that restore BRCA1/2 in carcinomas from women with germline BRCA1/2 mutations predict resistance to platinum chemotherapy and may also predict resistance to PARP inhibitors. These mutations were detectable only in ovarian carcinomas of women whom have had previous chemotherapy, either for ovarian or breast carcinoma.

press release: UCSF-led team decodes evolution of skin and ovarian cancer cells (squamous cell/serous cell)

"They worked with a type of skin cancer known as cutaneous squamous cell carcinoma, which has among the highest numbers of mutations of any cancer, and also with a common type  (blogger's note: assumption - serous cell type) of ovarian cancer."


"Using the new technique, the researchers were able to identify not just the mutations that differentiate two types of human cancer from normal cells, but the actual order in which some of the most key mutations occurred."
 ...................................................................................................

Temporal Dissection of Tumorigenesis in Primary Cancers

The article, "Temporal Dissection of Tumorigenesis in Primary cancers" is authored by Steffen Durinck, Christine Ho, Nicholas J. Wang, Wilson Liao, Lakshmi R. Jakkula, Eric A. Collisson, Jennifer Pons, Sai-Wing Chan, Ernest T. Lam, Catherine Chu, Kyunghee Park, Sung-woo Hong, Joe S. Hur, Nam Huh, Isaac M. Neuhaus, Siegrid S. Yu, Roy C. Grekin, Theodora M. Mauro, James E. Cleaver, Pui-Yan Kwok, Philip E. LeBoit, Gad Getz, Kristian Cibulskis, Jon C. Aster, Haiyan Huang, Elizabeth Purdom, Jian Li, Lars Bolund, Sarah T. Arron, Joe W. Gray, Paul T. Spellman, and Raymond J. Cho.
It appears in the July 2011 issue of the journal Cancer Discovery. See: http://dx.doi.org/10.1158/2159-8290.CD-11-0028

"Ovarian cancers generally show more complex karyotypic abnormalities than do cSCCs (13)." 

"We sought to validate our observations in an additional
cancer type. Recently, full genomic sequence and copy number
changes were determined for 10 ovarian serous adenocarcinomas
by The Cancer Genome Atlas Project. Ovarian
cancers generally show more complex karyotypic abnormalities
than do cSCCs (13). In the 3 samples with a clear, informative
CN-LOH event at 17p, we again found solid evidence
for complete loss of TP53 as the earliest event (Fig. 1D). These
initial events in ovarian tumorigenesis could not have been
determined through sequencing of precursor lesions and invasive cancers (1, 14), as the asymptomatic nature of early
disease precludes tissue collection." 

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."

Markman: KRAS Mutations in Ovarian Cancer -- Maybe Not

Expression of DNA repair genes in ovarian cancer samples: Biological and clinical considerations

Abstract

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas.  


ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis.

With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

abstract: DICER1 Mutations in Familial Multinodular Goiter (thyroid) With and Without Ovarian Sertoli-Leydig Cell Tumors

define: 

multinodular goiter - A multinodular goiter is  a thyroid gland that is usually enlarged and contains multiple thyroid nodules.

Pleuropulmonary blastoma (PPB) is a rare cancer originating in the lung or pleural cavity....
en.wikipedia.org/wiki/Pleuropulmonary_blastoma

 

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Objective To determine whether familial MNG  (multinodular goiter) with or without SLCT (Sertoli-Leydig cell tumor of the ovary) in the absence of PPB (pleuropulmonary blastoma)  was associated with mutations in DICER1. 

 

Conclusions DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

abstract: Mutation and Loss of Expression of ARID1A in Uterine Low-grade Endometrioid Carcinoma

Abstract:

ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry.

In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas. Mutational analysis of ARID1A was carried out in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors.

Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high-frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations, and tumors with ARID1A mutations showed complete loss or clonal loss of ARID1A expression.

In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A.

Medical News: SGO: Mutation Link to Ovarian Cancer Disputed - in Meeting Coverage, SGO from MedPage (KRAS mutation)

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 (pdf): Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer (Ontario, Canada study including demographics)

Abstract

BACKGROUND: The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.

METHODS: We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).

RESULTS: Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.

CONCLUSIONS: BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.

European Journal of Human Genetics - Abstract of article: On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

"The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual.............Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice."

Promoting genetic literacy: cancer control in the BRCA era - Cutting Edge - Cancer World (including Lynch Syndrome/spectrum of cancers)

Note: worth reading; covers a variety of concerns
 
IN BRIEF

• Accounting for around 5%–10% of all breast cancers, harmful mutations in BRCA1 or BRCA2 increase a woman’s chance of developing breast cancer over their lifetime by approximately five times compared to the normal population.
• Carriers of the harmful BRCA1/2 mutations are also approximately 10–30 times more likely to develop ovarian cancer, with these mutations accounting for around 10% of all ovarian cancers.
• There is no single BRCA mutation, but a wide variety of mutations on these two genes, many of which have yet to be recorded. Only some have been demonstrated to be harmful.
• BRCA mutations can also raise the risk of other cancers, including gastric, pancreatic, colon and prostate cancer, as well as melanoma and male breast cancer.
• Other ‘cancer genes’ include mutated APC genes, responsible for familial adenomatous polyposis, which lead to colon cancer, and mutated MLH1, MSH2 MSH6, or PMS2 genes, which are associated with hereditary non-polyposis colon cancer (HNPCC) (Lynch Syndrome), a syndrome that also raises the risk of endometrial (uterine), stomach, ovarian, small bowel (intestinal), urinary tract, liver, and bile duct cancers.

abstract + Free Full-Text (2010) Familial Pancreatic Cancer (includes discussion regarding BRCA/Lynch Syndrome/FAMMM and others)

Abstract: Pancreatic cancer’s high mortality rate equates closely with its incidence, thereby showing the need for development of biomarkers of its increased risk and a better understanding of its genetics, so that high-risk patients can be better targeted for screening and early potential lifesaving diagnosis. Its phenotypic and genotypic heterogeneity is extensive and requires careful scrutiny of its pattern of cancer associations, such as malignant melanoma associated with pancreatic cancer, in the familial atypical multiple mole melanoma syndrome, due to the CDKN2A germline mutation. This review is designed to depict several of the hereditary pancreatic cancer syndromes with particular attention given to the clinical application of this knowledge into improved control of pancreatic cancer.
Keywords: phenotypic and genotypic heterogeneity; high mortality; genetic counseling; biomarker paucity; FAMMM syndrome; Li-Fraumeni syndrome; Lynch syndrome; pancreatic cancer

The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients (study number 289 patients)

Note: MSH2/MSH6 are 2 of the Lynch Syndrome genes

Objectives

The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families.

Conclusions

Our data do not support screening for BRCA1/2 mutations in consecutive EC patients.

Who’s who in the world of personalised cancer treatments? - Cutting Edge Cancer World - Education & knowledge through people & facts