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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.


Genetic cancer classification | Basic concepts July 15, 2007

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

When talking about cancer, specialists often distinguish only two forms: hereditary (or inherited) and sporadic cancer.

In hereditary cancer, every body cell (somatic + germline) in the person’s body has a mutation in some highly penetrant gene (e.g. BRCA1 or 2). Because we inherit two copies of genes (or alleles) on separate chromosomes from our parents, the second copy usually is normal. But people who have inherited a constitutional germline mutation in tumor suppressor genes are one step closer to cancer than those who haven’t, because they generally follow the Knudson ‘two-hit hypothesis” and need inactivation of a second gene copy for cancer to develop. So, these persons are “one step closer to cancer” and the term hereditary cancer is mostly applied when we know the responsible gene, which commonly is tumor suppressor and disease phenotype is transmitted in an autosomal dominant manner with partial penetrance (but on the genetic level you’ll get recessive inheritance, cause disease is manifested when two copies of gene are faulty or so called loss of heterozygosity (LoH) is present). So, by the term of hereditary cancer we often mean “predisposition to cancer” (because we don’t inherit cancer – we inherit only predisposition to it).

Mutations in the currently identified inherited cancer predisposition genes are relatively rare and probably play a major role in the development of about 5-10% of all solid tumors and a smaller proportion of hematological malignancies. This is not big but well defined and very important proportion.

In sporadic cancer there are mutations only in somatic cells (diploid) of affected organ. These mutations usually are not inherited and are caused by environment or other factors. The genetic testing in sporadic cancer cases usually gives prognostic information about the course of disease, but don’t say anything about the recurrence in the future generations.

If you don’t attend hereditary cancer conference, the common course of talk will be as follows: hereditary cancers are rare (therefore not very important) and speaker tends to switch his talk mainly to sporadic, which constitutes more than 90 % of all cancer cases.

But there is a third very important group – familial cancer, which is caused by a mixture of environmental factors and variation in several low penetrance genes. We usually use this category when cancer occurs (i.e. clusters) in families more often than would be expected by chance and influenced by as-yet-unidentified genes, whose effects are not fully understood. As with hereditary cancer, these mutations are in every cell of a person’s body. But unlike hereditary cancer, carrying mutations in these genes poses only a slight risk of developing cancer. On GeneticHealth site there is a nice comparison of all these three subgroups.

Some claims that familial cancers account for 10-30% of all cancer, depending on a location site. Research of familial cancer is very hot topic now and some researchers hypothesise, that all cancer are genetic. New polymorphisms in low penetrance genes are constantly found and when our knowledge improves a proportion of so called sporadic cancer is rapidly shrinking. Of course, environmental factor are important in the development of cancer, but not all people develop cancer even if they are exposed to highly carcinogenic substances (e.g. tobacco smoke) – only susceptible with subtle changes in multiple low to moderate penetrance genes will be affected.

I think that better understanding of these variations and successfull implementation of that knowledge in clinical practice will be the most important advance in cancer research in a near future. An additional set of relatively common, low penetrance cancer predisposition genes remain to be identified that may contribute to a much higher proportion of cancers that do the high-penetrance cancer genes currently identified. Although relative risk for cancer in such persons is about 1.4-2%, but if you have changes in several low-penetrance genes, combined risk could potentially exceed the risk of highly penetrant genes, such as BRCA 1/2.

And I am ready to explore and face this field with my readers on medical and scientific blogosphere.

The pictures bellow should help to make a clearer idea (note the blurred boundary between sporadic and familial):