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Somatic mutations in cancer and genetic syndromes June 29, 2008

Posted by ramunas in cancer genetics, Ras-MAPK, Resources, sporadic cancer.

As for clinical geneticist, traditionally concerned more with germline (hereditary) mutations and disease, it might be strange to search through somatic mutation (or acquired) databases. But it is obvious that understanding of cancer genetics can not be limited to only germline or somatic mutations – it must be combined approach. And then you start to think in systemic way, or in other words, you think in pathways or patterns (pretty much the same way as main character from D. Aronofsky’s notorious “Pi” :) )

Anyway, currently I’m gliding through Ras-MAPK signaling pathway and in a future some posts will be related to it. Interestingly, lot of things in genetics are connected or in other ways, as a friend of mine once stated, “traditional genetics is dead:)

Just take a look: Ras-MAPK pathway is probably one of the most upregulated pathway in sporadic cancers. And there are bunch of syndromes with inherited altered mutations in a genes from there:

Among other symptoms, Neurofibromatosis type 1 have up to 13% risk for developing maligancy (mostly for MPNST), Costello syndrome have about 17% increased risk of cancer (particularly rhabdomyosarcomas, neuroblastomas and bladder Ca), in Noonan there is increased risk for juvenile myelomonocytic leukemia. Therefore lot of attempt must taken to perform targeted screening for these patients. LEOPARD (which is allelic for Noonan s. and stands for lentigines, ECG anomalies, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarded growth and deafness) and CFC syndrome seems do not have increased cancer risk.

For somatic mutation in cancer invaluable tool seems to be COSMIC database – Catalogue of Somatic Mutation In Cancer by Wellcome Trust institute. COSMIC is designed to store and display somatic mutation information and related details and contains information relating to human cancers. Enjoy.

Prostate Cancer | Old&New SNPs and deCODEPrCa February 15, 2008

Posted by ramunas in cancer genetics, familial cancer, genetic testing, hereditary cancer, prostate cancer, research, sporadic cancer.
1 comment so far

This week was undoubtfully very important in elucidation of genetic predisposition to prostate cancer. Three teams (two public and one private) reported their SNP studies in Nature Genetics.

A two-stage genome-wide association study (GWAS), lead by well known Cancer Research UK researchers dr. Rosalind Eeles and Douglas F Easton, was performed on Australian and UK men and confirmed previously associated genetic variants (SNP’s) to prostate cancer at 8q24, occurring in three distinct blocs, which were best “tagged” by SNPs rs6983267, rs1016343 and rs4242384 (as you know, our genome is fragmented and genetic information passes through generations by distinct “blocks” of DNA, called haplotypes, and which can be “marked/tagged” by representative spots, called “tag SNP” – a kind of genetic folksonomy marks) and 17q (a strongest association with rs7501939 (at 17q12) and rs1859962 (at 17q24) . Also several genetic variants on seven new loci on chromosomes 3 (rs2660753), 6 (rs9364554), 7 (rs6465657), 10 (rs10993994), 11 (rs7931342), 19 (rs2735839) and X (rs5945619) were identified, which could explain ~6% of the genetic risk for prostate cancer (a highly significant SNP rs10993994 in MSMB (beta-microseminoprotein) gene proximal promoter constitutes ~2% of risk).

Constantly innovative deCODE based on own results issued predisposition to prostate cancer test deCODE PrCa of 8 SNPs for $500, which is the second commercially available genetic test for prostate cancer after Focus5 test offered by Proactive Genomics. Two new SNP’s single-letter variations (rs721048 on chromosome 2 and rs5945572 on the X chromosome are also included in deCODEme genotyping service, and subscribers can check it out now.

These two SNPs confer relatively modest increases in risk – of approximately 20% and 15% per copy carried, respectively – but because they are also quite common they are each believed to contribute to about 5% of prostate cancer cases (via).

“The genetic testing market is highly competitive. No sooner does one company launch a first-of-its-kind test than another launches a similar one”, Hsien at EyeOnDNA notes about this new test.

Other study also confirms previously reported loci on 8q24 and 17q chromosomes and identifies new SNPs on 7 (rs10486567), 10 (rs10993994; strongest association) and 11 (rs10896449) chromosomes (overal 7 SNPs). Individual population attributable risk (PAR) for prostate cancer for each of the seven independent loci ranged from 8% to 20%.

These findings help clarify genetic structure of prostate cancer, shed light on plausible candidates gene regions and have implications for risk counseling, which can be of clinical importance when cumulative risk is appreciated.

Interestingly, all studies were performed using Illumina bead-chips platform.

Note: to associate any SNP with some condition a strict statistics must be applied: the results must meet or at least approach the “standart of genome-wide significance” with P value <10 minus 7 (0.00000001).

Colon cancer gene expression | Genomic Health January 30, 2008

Posted by ramunas in cancer genetics, colon cancer, genetic testing, sporadic cancer.

The producers (Genomic Health) of breast cancer recurrence 21 gene expression test Oncotype DX (launched in 2004) recently reported the results of two studies, which found genes that could help predict the likelihood of recurrence of and chemotherapy benefit for early-stage colon cancer (via).

Results of the studies were presented January 26, 2008 at ASCO GI, the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, in Orlando, Florida.

Both study reports used Genomic Health’s quantitative RT-PCR to analyze RNA expression for 375 cancer-related and reference genes from colon tumors of patients who were treated with surgery alone or with surgery and adjuvant 5-fluorouracil/leucovorin (5-FU/LV) chemotherapy (ref.).

In first study (765 + 270 patients) and researchers found 65 genes significantly associated with colon cancer recurrence across – the individual gene expression was associated with an up to 11-fold difference in the risk of disease recurrence (via).

The second study analyzed colon cancers from an additional 508 patients who were treated with surgery plus 5-FU/LV chemotherapy. Fifty six genes were discovered that were significantly associated with disease prognosis for stage II and III colon cancer

Fifteen of the 56 genes were also used as a preliminary model to stratify patients into recurrence-risk categories (via).

Overall, Genomic Health has completed four independent studies involving 1,851 colon cancer patients to evaluate a total of 761 genes. This data will support the selection of the final gene set (ref).

Not long is to wait for the new test (an analog to breast cancer Oncotype DX) to personalize treatment decisions for early-stage colon cancer patients.

Happy 2008! | And Briefly About 2007 December 31, 2007

Posted by ramunas in breast cancer, BT Test, cancer genetics, DiaGenic, familial cancer, genetic testing, MammaPrint, Oncotype DX, PC Detect, prostate cancer, sporadic cancer, technology.

(artwork by Hollis Sigler, 1948-2001)

Happy New Year 2008! Especially to all people, who encountered and battled cancer. Also for those who work to help fight this disease. Lot of advances in our understanding about this condition were achieved this year. It is too naive think that we could completely eliminate cancer, but it is very realistic to think that we can (and will able) to better predict and control this disease.

2007 will be known in history as a breakthrough in understanding of our (Humans: Homo sapiens sapientis) genome variation and enormous success in genome wide association studies (GWAS) for complex disorders ) cancer included (e.g. see my post about breast cancer).

2008 will be definitely an exciting journey through a highway (yet in a desert) of personalized genomics:

(from a movie Electroma, 2007)

I believe that individual molecular profiles will soon help to improve the early detection of cancer : over 50 novel DNA methylation-based biomarkers of breast cancer (by Orion Genomics) can replace mamography in a near future.

(courtesy of Biotage)

Also 37 gene expression markers from peripheral blood (by DiaGenic) will be offered in UK by Opaldia from 2008 (also covered by EyeOnDna, GeneticsAndHealth and MedGadget).

A new BT Test (by Provista Life Sciences) is designed to complement other testing methods to aid doctors in more accurately diagnosing breast cancer in its early stages, when life-saving treatment is most effective (via). The BT Test utilizes a proprietary algorithm to evaluate the levels and relationship of multiple, cancer associated protein biomarkers in blood serum. This data is coupled with a patient’s personal medical profile to generate a comprehensive report designed to assist healthcare providers in making an earlier diagnosis of breast cancer (via).

Two gene-expression assays, Oncotype DX and MammaPrint, have been developed and extensivelly reviewed in 2007, to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer. In the future, these tests may be useful in determining the need for systemic adjuvant therapy in such patients (ref.).

Unexpectedly, some years ago alterations in mitochondrial DNA – our reminder about The Seven Daughters of Eve – have been suspected to play an important role in the development and progression of cancer. Several mutations have been identified in a wide variety of human tumors, including breast, colorectal, ovarian, gastric, hepatic and esophageal cancers, as well as hematological malignancies [ref.]. Some studies this year points to the importance of the variants in D-loop in familial breast cancer.

Genomic alterations in a new cancer marker – nucleophosmin (NPM1) (by Ipsogen) – has an enormous impact in the biological study, diagnosis, prognostic stratification, and monitoring of minimal residual disease of various lymphomas and leukemias (especially acute myeloid leukemia (AML)). The discovery of NPM1 gene alterations also represents the rationale basis for development of molecular targeted drugs.

Panacea Pharmaceuticals (hm, what a name…) has initiated manufacturing of PC Detectsm kits, the Company’s diagnostic test for prostate cancer, under GMP condition. It based on detection of Human Aspartyl (Asparaginyl) beta-Hydroxylase (HAAH), a cancer biomarker. HAAH has been established as an excellent biomarker for many types of cancer, including prostate cancer. The protein is typically undetectable in sera from cancer-free individuals, thus, an elevated serum protein level of HAAH is highly diagnostic for cancer. PC Detectsm is recommended as an adjunct to the prostate specific antigen (PSA) test and the digital rectal examination (DRE), the currently recommended prostate cancer screening methods (ref.).

A booming field in micro-RNA and cancer field is expected to blossom in forthcoming years – microRNA-10b and breast cancer metastases is a recent example in Nature. It is truly biology’s Big Bang in our 21st century – The RNA revolution.

(photo from Economist)

Tumor immunology, with cancer immunoediting concept in ahead, T regulatory cells and advances in therapeutic cancer vaccines is an important future promise. Individualized cancer immunotherapy with RNA loaded dendritic cells (DC) vaccines (by Argos Therapeutics) is one of the opportunities and new generation of choices.

Complexities of BRCA genes December 4, 2007

Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, ovarian cancer, sporadic cancer.

There are some exciting news in cancer genetics. An extremely informative article about BRCA 1/2 genes mutations in different populations was published recently in Nature Reviews Cancer, which highlighted the complexity of BRCA mutation data and interpretation problems.

Inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes are the strongest indicators of breast and/or ovarian cancer risk. Prevalence of BRCA1 and BRCA2 mutations among high-risk cancer patients may vary by ethnicity, study inclusion criteria and mutation detection techniques.

In general, germline mutations in known breast cancer risk genes account for ~20% of breast cancers associated with family history. Aproximately 1-29% of such families will have mutations in BRCA1 gene and 1,5-25% in BRCA2 gene (ref.). As you’ve already noticed, there is wide variance, which is dependent on selection criteria, studied populations and technology used.

Moreover, there is a huge variation in penetrance (i.e. a proportion of persons who carry mutation and will develop disease). Studies show that the penetrance of deleterious BRCA1 and BRCA2 mutations is lower overall in a general population than in high-risk families, but the variability is broad and the confidence intervals are wide. One of the reason of such variability may be family-specific genetics and/or environment modifiers (the evidence for that is RAD51 polymorphism, which modify penetrance of BRCA2 (revied by GeneSherpa).

The most consistent and clearly written range I’ve found (and now use in practice) in a new edition of I.D.Young “Risk Calculation in Genetic Couseling“:

Cumulative risks for breast and ovarian cancer to age 70 years for BRCA1 mutation carriers average around 70-85% and 45-60%, respectively, for multiple-case (i.e. high risk) families, whereas average risks of 65% and 40% have been obtained for unselected (i.e. sporadic) cases. Comparable risks for BRCA2 carriers are 60-85% (breast) and 27%-31% (ovarian) for mulitple-case families and 45% (breast) and 11% (ovarian) for unselected cases.

As we approach the goal of personalized medicine, it is important to recognize the contribution of an individual patient’ s genotype to her (or his) breast cancer ovarian cancer syndromes include early age of cancer risk, as well as the gene–gene and gene–environment relationships that may modify mutation penetrance in each individual.

The results of sporadic breast/ovarian cancer studies suggest BRCA1 mutation frequencies ranging from 4 to 29% and BRCA2 mutation frequencies from 0.6 to 16% (ref.)

The important conclusion for clinicians is that it is likely most BRCA1 and BRCA2 mutations occurring in a clinical setting will be present in individuals with no family history of breast cancer.

Some BRCA1 and BRCA2 mutation carriers without family history of disease may have comparatively low (but still clinically significant) mutation-associated penetrance, whereas others may have uninformative family structures that do not reveal family history regardless of mutation penetrance, such as small size, few female relatives or patrilineal inheritance of the mutation (ref.).

One of the most useful ways to approach penetrance estimates is to examine founder mutations, or high frequency individual alleles that are particular to a specific population.

I’ve found very useful definition of founder mutation:

A recurrent mutation that occurs on a single haplotype in a population may be considered a founder mutation, while a mutation that occurs on more than one haplotype is considered to have occurred multiple times in the population history and is not a founder mutation (a haplotype is a set of nearby genetic markers that segregate together as a unit through generations) (ref.).

There is a schematic representation of most important known founder mutations:

And an excerpt from a table:

There are two common mutations of BRCA1 gene in Lithuania (the same as in Latvia and more or less in Poland, what reflect long coexistence of populations, although the origin is different – there are data of X and Y chromosome analysis in Baltic countries performed by my previous colleague), although I’ve found one protein truncating deletion not previously described anywhere (already submitted inquiry to BIC mutation database).

3 Genomic Tests for Therapy Decisions | Breast Cancer September 11, 2007

Posted by ramunas in breast cancer, cancer genetics, genetic testing, research, sporadic cancer.

During the first American Society of Clinical Oncology (ASCO) Breast Cancer Symposium researchers from The University of Texas M. D. Anderson Cancer Center presented two research updates on the genomic predictors in the breast cancer.

In one poster results from two studies involving 960 patients validating a Affymetrix U133 microarray-based 200-gene index test that predicts a patient’s response to hormone-suppressing therapy (sensitivity to endocrine therapy (SET index)) are presented. It was developed by M.D. Anderson in collaboration with Nuvera Biosciences Inc.
In these two studies, the Sensitivity to Endocrine Therapy (SET) Index score predicted distant relapse free survival (DRFL) among 453 patients who received tamoxifen, an anti-estrogen therapy, for five years, but revealed no prognostic information in the absence of endocrine therapy.

“We believe this is the first genomic test to predict sensitivity to hormone therapy independent of a patient’s prognosis if no post-surgical treatment is received,” (via)

Poster abstract here.

The other poster presents results from combined use of three genomic prognostic and treatment response predictors tests in lymph node-negative breast cancer.

The 3 clinical outcome predictors are;

  • A 30-gene predictor of the cancer’s sensitivity to chemotherapy developed by M.D. Anderson investigators.
  • The 200-gene index (SET) of sensitivity to hormone (endocrine) therapy developed by M.D. Anderson in collaboration with Nuvera Biosciences Inc.

The ASCO poster describes gene expression profiles analyzed from 198 patients with stage 1 or stage 2 breast cancer that had not spread to the lymph nodes and who had not been given chemotherapy or endocrine therapy after surgery.

Among the 198 patients, 55 were predicted to be at relatively low risk that the cancer would return. Of those low-risk patients, 21 were predicted to have cancer vulnerable to chemotherapy and 16 were predicted to have tumors susceptible to endocrine therapy. Two had cancers sensitive to both therapies.

Of the 143 patients predicted to have a high risk of recurrence, the analysis predicted 109 had cancer unlikely to respond to endocrine therapy, 64 were predicted to be insensitive to chemotherapy, and 38 were predicted to be unlikely to respond to both therapies (via).

Conclusion: A substantial proportion of low risk-patients appears to be highly sensitive to systemic treatment modalities, and many high-risk patients are predicted to be refractory to existing therapies. Simultaneous prediction of risk of recurrence and sensitivity to therapies may lead to more appropriate treatment decisions for individuals because the predicted sensitivity to chemotherapy and endocrine therapy could be weighed against the risk of relapse.

“Let’s say a new patient has a needle biopsy performed, and the microarray analysis of the tumor’s gene expression predicts she is at low risk of recurrence and also has cancer that is insensitive to both chemo- and endocrine therapies; in this cases the best option is relatively clear; surgery alone. However, it is important to know the sensitivity of the cancer to chemo- or endocrine therapies independent of the risk of recurrence alone. For example, a person even with low risk for cancer recurrence might elect to receive further therapy if her cancer is known to be highly susceptible to treatment.” , investigators explain.

Poster abstract here.

A collection of posters from section “familial breast cancer/genetic testing” available here.

New Molecular Test For Postmenopausal Breast Cancer | Mammostrat September 6, 2007

Posted by ramunas in breast cancer, mammostrat, sporadic cancer, technology.

The Molecular Profiling Institute, Inc. has just announced that they are now providing Mammostrat, a new molecular-targeted breast prognostic test, to breast cancer patients, nationwide in the USA. The Mammostrat prognostic test utilizes five immunohistochemical (IHC) biomarkers a diagnostic algorithm.to classify patients into high, moderate, or low-risk categories for disease recurrence.

Acctually, it is not a true genetic test. Mammostrat is a five-antibody immunohistochemistry (IHC) prognostic test for postmenopausal, estrogen receptor-expressing, hormone receptor-treated (tamoxifen) breast cancer patients with node-negative disease who will receive hormonal therapy and are considering adjuvant chemotherapy. It utilizes standard paraffin-embedded tissue (via and via) .

The five markers are as follows:

  • p 53 , which is known to play a central role in cell cycle regulation and mutations in p53 contribute to tumor formation (aka “the Guardian of Genome”)
  • HTF9C , which is co-expressed with proteins that are involved in DNA replication, implicating HTF9C in DNA replication and cell cycle control.
  • CEACAM5 , which is normally expressed in embryonic tissue and is aberrantly expressed in some cancers.
  • NDRG1, which is expressed under conditions of hypoxia and other stresses. It may have a role in helping tumors survive under the hypoxic, stressful environment confronting aggressive tumors.
  • SLC7A5, which is involved in nutrient transport. Over-expression of SLC7A5 could help sustain the high growth rate of cancer cells by increasing a cell’s ability to consume nutrients.

Mammostrat testing is performed by staining the supplied sections and appropriate control tissue with the five Mammostrat antibodies. A trained pathologist will then score the stained slides according to established criteria. A “0″ for negative staining or a “1″ for positive staining for each antibody will be entered into the AGI algorithm to calculate a “Risk Index.” The Risk Index value will be used to classify the patient as low, moderate, or high likelihood of breast cancer recurrence. The ordering pathologist will receive a report similar to the sample report shown here. The Mammostrat report will list the staining result for each antibody, the Risk Index category (i.e. low, medium, or high) and an interpretation of what the score means for the patient.

Pathologists, oncologists and patients should use the Mammostrat test results in conjunction with other clinical information to help select amongst treatment options (via).

Because Mammostrat uses traditional immunohistochemistry technology, the test is expected to be significantly less expensive than existing molecular-based, prognostic tests for breast cancer and is typically covered by insurance.

“Mammostrat’s cost-effective, molecular-targeted analysis enables MPI to provide the test at a significant discount compared to our competitors. Moreover, test results will be available quickly — an average of seven business days — versus two weeks for alternative, comparable tests.” , says Todd Maney, Ph.D., Vice President of New Product Development.

The test was developed by Applied Genomics, Inc (AGI). who rigorously translated recent genomic insights in cancer into a novel immunohistochemistry test. Mammostrat test results have been validated using over a thousand patient samples in North America.

AGI also has developed PulmoType and PulmoStrat IHC based antibody tests for lung cancer.

The standard of care for most of postmenopausal women with estrogen receptor expressing, node negative breast cancer is surgery to remove tumor followed by hormone signaling targeted therapy (e.g. tamoxifen or aromatase inhibitors) (ref.).

The prognosis for this group of early stage, estrogen receptor positive breast cancer patients is considered favorable with approximately 90% or more of these patients surviving five years and longer. However, several studies have demonstrated that outcomes can be further improved by treatment with cytotoxic chemotherapy. Since it is clear that most patients will remain disease free in the absence of additional therapy it is likely that cytotoxic therapy is only important for a small subset of these early-stage cancers. Since chemotherapy comes with difficult side effects (e.g. nausea, hair loss, severe fatigue) and long term risk of cardiovascular complications and secondary tumors, the decision whether to use adjuvant chemotherapy is difficult and controversial. The potential benefit of using Mammostrat testing is to identify those patients at high risk of cancer recurrence and therefore more likely to benefit from additional chemotherapy as opposed to those patients at low risk of recurrence who may choose to forgot chemotherapy.

I think it would be of interest to include these protein encoding genes into some gene expression profiling test as well.

A BRAF Story | Colorectal, Thyroid CA and Melanoma September 6, 2007

Posted by ramunas in cancer genetics, colon cancer, colorectal cancer, genetic testing, hereditary cancer, HNPCC, sporadic cancer.

For the first time I’ve read about BRAF oncogene in a poster presented during one of the European Society of Human Genetics conference, probably in Amsterdam, Holland. It appeared that a single amino acid substitution (p.V600E), a hotspot point mutation, is an useful marker to exclude HNPCC (hereditary non-polyposis colorectal cancer). Interestinlgy, this somatic mutation of BRAF gene, which belongs to the RAF family of protein kinases from the RAS/RAF/MAPK pathway, is more than 90% present in sporadic colorectal cancers with methylated hMLH1 gene. Therefore, if you have access to a tumor DNA after simple PCR test you can exclude or suspect hereditary form of this cancer. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer (via).

Obviously, the confirmation should be done by testing for germline mutations mismatch repair (MMR) genes (mostly MLH1, MSH2, MSH6). Also, immunohistochemistry may point you which protein is missing. The Bethesda guidelines , original (1997) and revised (2003), are designed to select cases for analysis of microsatelite instability (MSI) features of tumor, but testing for BRAF mutation can yield additional and faster information.

Conventional strategy for genetic testing of affected individuals from families with suspected hereditary non-polyposis colorectal cancer (source):


Screening of mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC, one article states.

That is a story about colorectal cancer, but it was interesting for me to find out, that the same mutation of BRAF oncogene can be present in thyroid cancer. That may be useful in predicting the level of aggression of thyroid cancer and help guide treatment options and follow-up care, says the new research paper published in the September issue of the “Annals of Surgery”.

Researchers concluded, that BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

Study author, Kebebew E, explained that identification of the mutation in patients with thyroid cancer could be very useful in a variety of ways. For example, patients with the mutation may be candidates for a more aggressive approach to surgery, such as removing the central lymph node along with the diseased thyroid, to avoid the possibility of metastasis following surgery. BRAF V600E testing could also be useful for deciding between low- or high-dose radioiodine ablation therapy.

Other BRAF mutations are found in melanoma and BRAF possitive tumors may be more sensitive to a new class of drugs – protein MEK inhibitors (such as PD0325901, developed by Pfizer Research and Development).

Hereditary Cancer Public Perception | Cancerbackup August 13, 2007

Posted by ramunas in cancer genetics, familial cancer, hereditary cancer, media, sporadic cancer.

There were recently data released from survey performed by information charity Cancerbackup and Genes Reunited during collaborative What Now? campaign, which is aimed to highlight the myths that exist around cancer and genetics.

This survey reveals the unnecessary worry that exists because people overestimate their cancer risk based on their family history.

Of over 1,000 people that responded to the survey 60% incorrectly thought that family history was the biggest risk factor for cancer and only 15 per cent knew that it is actually age – two thirds of cancer incidence is in people over 65-years-old, says MedicalNewsToday.

I generally look quite carefully to such public surveys and media trends for interpreting results out of context – it is easy to dismiss important findings then.

It is now well established that genetic factors play an important role in causing cancer, therefore arguing that most cancer is non – genetic can be confusive both for public and other health care providers. “All cancer is genetic but some cancers are more genetic than others”. That actually means , that in most cases the causal mutations are not inherited but are acquired somatically, possibly as part of the normal aging process or as a result of prolonged exposure to particular carcinogens. Saying “genetics” does not necessarily means “something inherited”.

The cancer risk perception is a complex and personal feeling, and depends on a family history. Therefore from these (only) 1000 responders there could be a proportion of people with a strong family history, which naturally experiencing higher family history attribution. I remember one of my patient, who came and said – I definitely have a mutation – and she was right, because her mother, maternal aunt and grandmother died of breast cancer in an early age and she was also affected. For families like this cancer family history is really number one risk factor.

Cancer is so common that probably everyone of us has (or had) some relative with this disease. Some common cancers in the family may have occured by chance, but again, age is an important factor, which could indicate that cancer is occurring due genetic predisposition: young age is considered to be <50 years for breast, stomach, pancreas, bowel and prostate. For ovarian cancer, occurrence in an older age is still likely to be significant factor, if there are other family members affected with either ovarian or early breast cancer. Therefore, evaluating family history, the important features suggestive of an inherited susceptibility to cancer are (ref.):

  • early age of onset
  • bilaterality of disease (i.e. multiple primary tumors)
  • multiple cases on one side of the family (two or more first/second-degree relatives):

The vast majority of people realized that it is not just breast cancer that can occur because of an inherited genetic link. However, they didn’t realize that in order to suspect such a link, generally the same type of cancer (or cancers that are known to run together such as breast and ovarian or bowel and womb cancers) would need to occur in family members on the same side of the family (via).

  • other related early-onset tumors (“patterns” of associated cancers, e.g. breast and ovarian, colon and endometrial)
  • rare cancers (e.g. two or more relatives with the osteosarcoma).
  • ethic origin (Ashkenazi, Icelandic, Eastern European, Dutch etc).

Ageing is definitely an important risk factor, and cancer risk increases with age, with the highest incidence occurring over age 65 (64% (64 in 100) of all newly diagnosed cancers occur in people aged 65 years or more [via]). This may be due to less affective immune responses in the elderly or a lifetime of exposures. Probably, a cancer is a natural evolutionary fate of a cell in multicellular organism.

It is important to remember some sobering cancer risk factors (source: Offit, 1998):

  • diet – 35% (mainly alcohol, high protein intake, smoked/curred food, high fat intake)
  • tobacco use – 30% (mouth, pharynx, larynx, esophagus, stomach, lung, kidney, pancreas, bladder, cervix (sic!)).
  • hereditary factors – 5-10%
  • occupational exposures – 5%
  • radiation – 1-2%
  • viruses – 1-2%
  • miscellaneous – 16-23%

Bolded factors (65%) are important modifiable lifestyle factors for general population and tobacco is a single most important avoidable cancer-causing agent. However, the extent to which lifestyle changes can modify the cancer risk in individuals with inherited predispositions to cancer is unclear.

When asked what percentage of cancers occur because of a known inherited genetic link, only 13 per cent of people knew that just 5-10 per cent of all cancers are known to be hereditary. Furthermore, a quarter of people thought that between 50 – 100 per cent of cancers are hereditary (via).

Yes, that is true. But again – there is another type of cancer – familial, which could account up to 30% of cases. For example, up to 27% of breast cancer can be attributed to heritable factors from twin studies. Familial type refers to multifactorial inheritance, implying the interaction of additive polygenes with the environment, and probably plays a role in around 20-25% of cases.

It is important to remember general population risks (Western societies)

  • lifetime risk for any cancer -(1/3 – for women, 1/2 – for men
  • breast cancer (female) – 1/10 – 1/12
  • prostate cancer (asymptomatic) – 1/3
  • prostate cancer (clinicaly diagnosed) – 1/10
  • colon cancer – 1/25 – 1/50
  • ovarian cancer – 1/70
  • proportion of common cancers which is inherited – <1/10.

A staggering 91 per cent of people surveyed in a Cancerbackup poll on Genes Reunited’s website, thought that if one of their relatives had cancer, they are at a greater risk than average of getting it themselves. In actual fact in the majority of cases this would not significantly increase someone’s risk at all.

Again, I would interpret this with caution. Family history is an important risk factor for breast or ovarian cancer.

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one first-degree relative with ovarian cancer, cancer.gov claims.

So, a family history of ovarian cancer increases the risk by threefold, which, I think is not so unsignificant factor.

Also, in a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2). Risk increases with the number of affected relatives and age at diagnosis.

Textbooks (this and this) states, that the presence of a first-degree relative with breast cancer increases the risk 1,5-4.0-fold, depending on the age of the affected family member.

Having one affected first-degree relative increases the risk of colon cancer by three- to fourfold and having several relatives with colorectal cancer may be consistent with a hereditary cancer syndrome, Katherine Schneider writes.

Obviously, one or two cases of cancer in a family does not necessarily mean that there is a hereditary cancer syndrome in that family, but familial cases are also important to distinguish.

In conclusion, patient concern for cancer is common and valid reason for referral to genetic counseling. About 60% of women are referred to a familial breast cancer clinics due to their own initiatives. It was already shown, that from clinical attendees with a family history of breast cancer in UK, only 25% belonged to high risk, 25% had population level or lower risk, and 50% reached sufficient risk level for screening. “A women who has a low risk of being cancer-prone, but who is worried by her family history, should have access to consultation”, Eisinger et al. states. Often risk assessment alleviates fear and anxiety. Genetic counseling and testing generally results in lower psychological distress, both for those individuals who test negative and those who test positive.

Dr. James Mackay, Clinical oncologist and medical director of Opaldia, a private UK genetic testing company, and scientific advisor for a private polish genetic testing company Read-Gene, highlights some important questions of cancer genetics, which I’ve found in Cancerbackup YouTube account:

Anyway, I’ve missed more opinions of other independent clinical cancer geneticists, especially from academical setting.

Characteristics of Hereditary, Familial and Sporadic Cancer Syndromes August 1, 2007

Posted by ramunas in basic concepts, cancer genetics, familial cancer, hereditary cancer, sporadic cancer.

In a recently published recommendations for risk assessment and genetic counseling for hereditary breast and ovarian cancer (HBOC) in a Journal of Genetic Counseling, there is a very useful definition of 3 main type of cancer (from a geneticist point of view):
I. “Hereditary Cancer type” characteristics:

  • Apparently autosomal dominant transmission of specific cancer type(s)
  • Earlier age of onset of cancers than is typical
  • Multiple primary cancers in an individual
  • Clustering of rare cancers
  • Bilateral or multifocal cancers
  • First degree relatives of mutation carriers are at 50% risk to have the same mutation
  • Incomplete penetrance and variable expressivity, such that obligate carriers of the family mutation may be cancer-free and the age of diagnosis of cancer among relatives will vary
  • Those who do not have the familial mutation have the general population risk for cancer

II. “Familial Cancer type” chatacteristics:

  • More cases of a specific type(s) of cancer within a family than statistically expected, but no specific pattern of inheritance
  • Age of onset variable
  • May result from chance clustering of sporadic cases
  • May result from common genetic background, similar environment and/or lifestyle factors
  • Does not usually exhibit classical features of hereditary cancer syndromes

III. “Sporadic Cancers type” characteristics:

  • Cancers in the family are likely due to nonhereditary causes
  • Typical age of onset
  • Even if there is more than one case in the family, there is no particular pattern of inheritance
  • Very low likelihood that genetic susceptibility testing will reveal a mutation; testing with available technology/knowledge level will likely not provide additional information about cancer risk.

This classification can help in quantifying risks to individual family members and developing a plan for cancer screening, prevention, risk reduction and psychosocial support and counseling. It also helps in the determination of whether genetic testing is appropriate for the family, and if so, which relative(s) would be the appropriate individual(s) to test. Unfortunately, the separation of families into hereditary, familial, and sporadic cancer is often not precise.

With a growing knowledge in low penetrance genes those families which were regarded as sporadic could be reclassified to familial cases. For more information please also take a look at my first post on this blog.


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