Tumor resistance to chemotherapy is an often failure of successive treatment (together with adverse effects).

As you know, BRCA2 mutations are associated with an increase in breast and ovarian cancer risk, as the gene’s normal function is to repair damaged DNA. But these cancer-causing faults are bad news for the tumour itself, as they also render it sensitive to DNA-damaging chemotherapy drugs like cisplatin. Unfortunately, many BRCA2 tumours develop resistance to cisplatin (ref.).

(BRCA2 repairs a stretch of DNA; source)

Interestingly, the researchers found that, when exposed to cisplatin, some ovarian cancer cells develop secondary mutations on their BRCA2 gene that restore the gene’s ability to repair DNA (via). This is called positive mutation in general genetics – a mutation which improves adaptive properties of a cell (if we look from a cancer cell perspective).

The discovery raises the possibility that blocking BRCA2 function in such patients might allow doctors to overcome drug resistance and continue with cisplatin treatment. And maybe this mechanism will be true to other DNA-repair genes such as BRCA1, which may help explain drug resistance to a variety of cancers (via).

Another study finds the similar mechanism involved in resistance to PARP (Poly(ADP-Ribose) polymerase) inhibitors, a new class of drugs which are known to be more effective in BRCA1/2 mutation cases, because they work by selectively killing cells which have no functioning BRCA gene.

These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2 (ref.). Sure, therefore it is featured by Nature.

Next week I’m going to International Collaborative Group on Familial Breast and Ovarian Cancer (ICG-FBOC) meeting (9th symposium) named “Looking to the future cancer diagnostics & treatment: the impact of genetics“ in Cyprus (Κύπρος), Larnaka (Λάρνακα). There is going to be an extensive programme with the presentations of well known researchers from UK (Manchester, London), Norway and Greece. I look really forward to meeting these people and listen to their presentations.

If anyone of my readers are going to be there – please drop me a note – that will be nice to meet you there.

There are data accumulating, that having BRCA1/2 mutation from a clinical point of view is not worse that not having it and being affected by breast or ovarian cancer.

There was a study published in 2oo7 summer and discussed, which showed that women mortality from breast cancer is similar for carriers of a BRCA founder mutations and noncarriers (at least in Israeli).

And now, a new 2008 study found, that BRCA1/2 mutation even increases survival in ovarian cancer patients (Ashkenazi)- after 5-years, 46% of the carriers were still alive, compared with 34.4% of the noncarriers. This may be due to distinct clinical behavior and/or to a better response to chemotherapy. (ref.)

I think this is another pros for genetic testing with relaxed criteria (and definitely good news for a BRCA patients), since the main drawback of being BRCA mutation carrier is increased risk for an early breast/ovarian cancer compared with general population, and identifying of high risk patients before the disease strikes could prevent disease and improve survival.

However, I personaly think that present mutations detection fees are overpriced – and I believe that in a very near future there will be a dramatic decrease for all molecular genetic testing prices. A two approaches could be possible, IMHO, (i) a complex (sequencing of all coding regions/whole genome) and (ii) a simple – exploiting already existing technology more effectively and creatively in a cost effective way. I vote for a Simple Genetics

Here is probably the most accurate breast&ovarian cancer risk/mutation probability calculation web-application released from Cambridge University Genetic Epidemiology Unit – BOADICEA.

BOADICEA is a computer program that enables the user to estimate BRCA1/BRCA2 mutation carrier probabilities and breast/ovarian cancer risks based on polygenic model. The BOADICEA Web Application (BWA) has been designed in collaboration with clinical geneticists and researchers, in order to make BOADICEA risk estimations much quicker and easier.

It differs from available (BRCAPRO, Gail, Couch, Frank, Manchester model etc.), since it assumes not only high penetrance genes (eg. BRCA) for risk calculation, but also contribution of other low penetrance genes, most not yet identified (thus polygenic).

For more than a year lot of users tested beta phase (I am grateful to Alex Cunningham, the main developer and programmer, for letting to participate during this phase) and the final version was released. Excellent work, I would say!

The approach was first described by Antoniou AC et al. in 2004 and it was shown that overall familial risks of breast cancer predicted by this model were close to those observed in epidemiological studies.

Anyone can register to use the program including researchers, healthcare professionals and the public. However, if you are a member of the public and you are concerned about your family history, it is strongly advised that you seek guidance first from your general practitioner (see Advice for members of the public).

N.B. Be aware, however, that current model is based on genetic epidemiology of UK population. For other populations it may give not correct risk estimation.

P.S. I would like to apologize my readers for not posting long – I’m completely drowned in the final year of my residency and end of a year…

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).

Recently guidelines on risk assessment for inherited gynecologic cancer (Hereditary Breast/Ovarian Cancer (HBOC) and the Lynch/Hereditary Non-Polyposis Colorectal (HNPCC)) predispositions were published by The Society of Gynecologic Oncologists (SGO).

Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained (ref).

Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes (ref).

Up to 10% of breast cancer and 10-15% of ovarian cancer cases are related to BRCA 1/2 genes mutations (“faulty genes”), so called HBOC syndrome.

Mutations in BRCA1 genes confers a 39% to 46% chance of a woman developing ovarian cancer and a 65% to 85% risk of a woman developing breast cancer by age 70 years. The BRCA2 gene is associated with an ovarian cancer risk for 10% to 27% and a breast cancer risk for 45% to 85% by age 70 years (ref., subscription needed).

For comparison, overall life time breast cancer risk in the western population is 10-12%, and ovarian 1,5-2%.

The SGO guidelines recommend genetic risk assessment for women with a 20% to 25% likelihood of having BRCA1 or BRCA2 mutations. For patients whose probability of predisposition is greater than 5% to 10%, the guidelines suggest that genetic risk assessment “may be helpful.”(ref.)

It is a new thing (“20-25%”) for me, because to my knowledge, a guidelines in USA set by the American Society of Clinical Oncology (ASCO) suggested a 10% likelihood of finding BRCA1/2 mutations to undertake genetic testing. A stringent 20% likelihood threshold of having BCRA mutations is already applied in UK.

Lynch/HNPCC syndrome is caused by germline mutations in genes that oversee DNA mismatch repair. The family predisposition conferred by mutations in genes MLH1, MSH2, or MSH6 includes not only colorectal cancer and cancers of the endometrium but also cancers of the ovary, stomach, small intestine, and other organs. Women with one of these mutations have a 42% to 60% likelihood of developing endometrial cancer and a 9% to 12% chance of developing ovarian cancer by the age of 70 years. Their lifetime risk for colorectal cancer is 40% to 60 (via).

The SGO statement divides the Lynch/HNPCC guidelines into those for patients with a 20% to 25% chance of having the inherited predisposition and those with a greater than 5% to 10% chance. The guidelines reflect both personal and family profiles, with the “revised Amsterdam criteria” included for the higher-risk group.

“revised Amsterdam criteria” for HNPCC are as follows (ref.):

• Patients have at least 3 relatives with a Lynch/HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis) in 1 lineage,
• One affected individual should be a first-degree relative of the other 2,
• At least 2 successive generations should be affected, and
• At least 1 HNPCC-associated cancer should be diagnosed before age 50 years.

Performing the genetic testing and finding out that a patient does or does not have a genetic mutation can allow us to reduce risks for other related cancers, and can have tremendous impact for the patient’s family members if a mutation is found.

When assessments identify women at high risk for these cancers, they could receive magnetic resonance imaging breast screening, colorectal screening with colonoscopy, and preventive surgery, but the medical community must become aware of the importance of these strategies in improving individual outcomes. (ref.)

As you may already noticed, in the beginning of this year the most comprehensive open-access online BRCA1/2 mutation database Breast Cancer Information Core (BIC) - an international collaborative effort hosted by NHGRI – added significant improvements and more are on the way:

Changes to the BIC include redesigned search tools, a field classifying the “clinical importance” of each mutation and inclusion of additional information on a subset of mutations. Expect to see additional cosmetic and content changes in the coming months.

A field of “clinical importance” is worth further in deepth analysis. There are three categories:

1. Clinically important (“Yes”):

Clinical

• Based on available data, it is the opinion of the BIC steering committee that sequence change of this type interferes with gene function and results in an increased risk of cancer.
• All clinically important alleles may not confer the same degree of risk and the precise degree of risk associated with this mutation cannot be estimated.

Basic Science

• • This sequence change may abolish some or all of the normal functions of this gene. Some alleles may produce a stable mutant mRNA or protein.
  • However, many mutant alleles of this type do not produce mRNA or the encoded protein is unstable.

2. Not clinically important (“No”):

Clinical

• Based on available data, it is the opinion of the BIC steering committee that this sequence change is neutral or of little clinical importance.
• Some sequence changes of this type may be associated with modest increases in cancer risk.
• Some individuals carrying this sequence change also could carry a clinically significant mutation.

Basic Science

• • It is likely that the mRNA and protein produced by this allele generally functions similar to wild type.
  • However, this protein contains multiple functional domains and some biological functions of this allele may be compromised.

3.”Unknown”:

• • Insufficient data exist at this time to allow assessment of the clinical or functional implications of this sequence change.
  • Although we attempt to update the BIC database on a regular basis, we also suggest searching the medical literature (PubMed – Google) to determine if new information is available on this sequence change.

BIC is very useful database. And those new improvements will shed some light on polymorphisms. But variants of unknown significance (VUS), which are polymorphisms of uncertain clinical importance and account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations, still could be not easy thing to interpret without functional expression studies, phylogenetic analysis and other approaches.

More than 600 mtations in BRCA1 genes and more than 450 in BRCA2 genes are reported to date. Only about 2-3 of all breast cancer cases can be attributed to inherited mutations in BRCA1/2 genes, and up till 15% of all ovarian cancer cases (10% – BRCA1, 5% – BRCA2), unselected for ethnicity [ref.]. The overall frequency of of BRCA1 gene mutation is 0,0007 – i.e. about one woman in 700 is a heterozygous carrier [ref.] and somewhat less for BRCA2. Interestingly, that irrespective of family history between 20-25% of women diagnosed with ovarian cancer between the ages of 41 and 50 will carry a BRCA1/2 mutation [ref.].