Genetic testing for inherited predisposition to cancer

First Genetics Laboratory strongly recommends conducting testing for hereditary predisposition to oncological diseases only after consultation with a clinical geneticist.

Article contents

What is Hereditary Cancer Syndrome?
Why is genetic testing for hereditary cancer syndromes important?
Does someone who inherits a cancer susceptibility variant always get cancer?
What does the testing for hereditary predisposition to cancer include?
Who should consider genetic testing for hereditary cancer syndromes?

What is Hereditary Cancer Syndrome?

Hereditary Cancer Syndrome

It is a condition caused by changes in the structure and/or regulation of a gene (number of genes), characterized by an increased risk of developing cancer and having several target organs.

In most cases, such genetic disorders are usually inherited from generation to generation, but in ~ 20% of cases, the genetic alteration can occur de novo, i.e., for the first time. Certain cancer patterns may be observed in families with a hereditary predisposition. These patterns include several close family members (such as mothers, daughters, and sisters) with the same type of cancer, the onset of a tumor at an early age, or the presence of two or more cancers in the same person.

Approximately 10% of all cancer cases are hereditary. This percentage is much higher for some cancers: about 20% of all neuroendocrine tumors are hereditary/familial forms; 20-25% of ovarian cancers are due to hereditary predisposition, i.e., genetic disorders passed down from generation to generation.

Why is genetic testing for hereditary cancer syndromes important?

Most of the genes responsible for hereditary cancer syndromes have been identified.

Testing whether someone carries a pathological variant in one of these genes can confirm if the disease results from a hereditary cancer syndrome. Genetic testing is also done to determine if family members who have not (yet) developed cancer have inherited the same variant as a family member known to carry the pathological (cancer-predisposing) genetic alteration.

A timely diagnosis of inherited cancer susceptibility syndrome allows doctors and patients to take preventive measures, identify and predict possible cancer and consider various reproductive options to prevent the transmission of pathological genetic variants to descendants.

Does someone who inherits a cancer susceptibility variant always get cancer?

No. Even if there is a genetic predisposition to cancer in the family, this does not necessarily mean that everyone who inherits this genetic alteration will develop tumors / be diagnosed with cancer.

Several factors influence whether a person with a pathological genetic variant will develop cancer.

One of them is the penetrance of the variant. When not all individuals who carry a pathological variant develop a disease associated with that alteration, it is said to have incomplete or reduced penetrance.

Hereditary cancer syndromes can also vary in their expressivity. People who inherit a pathological genetic variant may differ in the extent of manifestation of the signs and symptoms of hereditary cancer syndrome, including the development of associated tumor types.

Lifestyle factors and environmental risks can also influence disease expression.

What does the testing for hereditary predisposition to cancer include?

Genetic testing for inherited cancer predisposition includes 90 genes associated with 41 hereditary cancer syndromes.

This assay analyzes the complete coding sequences of 90 genes associated with the following hereditary cancer syndromes:

Melanoma-astrocytoma syndrome
Birt-Hogg-Dubé Syndrome
Von Hippel-Lindau Disease
Hereditary breast cancer and/or gynecologic cancers (moderate-penetrance genes)
PTEN Hamartoma Tumor Syndromes (Including Cowden Syndrome)
DICER1 syndrome
Fanconi anemia
Familial adenomatous polyposis and Attenuated familial adenomatous polyposis
Familial Atypical Multiple Mole Melanoma syndrome
Familial medullary thyroid cancer
Basal cell nevus syndrome (Gorlin syndrome)
Hereditary breast and ovarian cancer syndrome
Diffuse gastric and lobular breast cancer syndrome

Hereditary leiomyomatosis and renal cell cancer
Hereditary/Familial lung cancer
Hereditary neuroblastoma (juvenile tumor)
Hereditary papillary renal cell carcinoma
Familial Juvenile polyposis
Li-Fraumeni Syndrome
Lynch Syndrome
MUTYH-associated polyposis
Multiple Endocrine Neoplasia Type 1 (MEN1)
Multiple Endocrine Neoplasia Type 2A, 2B (MEN2A, 2B)
Multiple Endocrine Neoplasia Type 4 (MEN4)
Neurofibromatosis type I
Neurofibromatosis type II
Hereditary/Familial paraganglioma and pheochromocytoma Syndrome
Familial isolated pituitary adenoma

Peutz-Jeghers Syndrome
Tuberous sclerosis complex
Retinoblastoma
Rhabdoid tumor predisposition syndrome
Schwannomatosis
Hereditary prostate cancer
Wilms' tumor
Bloom syndrome
BAP1 Tumor Predisposition Syndrome (BAP1-TPDS)
Familial gastrointestinal stromal tumor
BRIP1-associated Hereditary ovarian cancer
Hereditary oral squamous cell carcinoma
Muir-Torre Syndrome

Who should consider genetic testing for hereditary cancer syndromes?

The table below lists the red flags suggesting hereditary cancer syndrome. However, the signs below cannot 100% guarantee the presence or absence of a particular hereditary cancer syndrome. Laboratory First Genetics recommends considering genetic testing for inherited cancer susceptibility syndromes after genetic counseling. A geneticist will help you understand whether there are real risks of a hereditary cancer syndrome in the family and explain how testing will be performed and what results to expect.

Red flags

Notes

Patient

Early onset tumor/patient’s young

Tumors in patients younger than 45 years for breast age cancer, prostate cancer, colorectal cancer, endometrial cancer, ovarian cancer; CNS tumors in patients younger than 25 years old, juvenile forms of malignant neoplasms.

Bilateral and multifocal (synchronous and metachronous) tumors

Bilateral breast cancer, synchronous/metachronous colon or lung cancer, combination of breast/ovarian cancer, colon/ endometrial cancer, >15 gastrointestinal polyps, >5 hamartoma or juvenile polyps of the gastrointestinal tract.

Tumors rare for gender

Male breast cancer

Tumors with rare histopathology

Medullary thyroid cancer, retinoblastoma, sebaceous gland carcinoma/adenoma

Congenital anomalies/unusual features in the patient’s phenotype

Café au lait spots, macrocephaly, dolichocephaly, pigmentation of the oral mucosa, cleft palate / lip, multiple skin fibromas, lipomas; marfanoid habitus (long arms, arachnodactyly, small mouth with crowded teeth, high palate), etc.

Ethnic Origins

Some ethnic groups have a high percentage of «founder mutations», which as a result leads to an increased risk of having a genetic disorder. These ethnic groups include Ashkenazi Jews, Amish, Inuit, Danes, Finns, Pakistanis, Irish, indigenous people of Newfoundland and Labrador (eastern province of Canada), and some others.

Family

First-degree relative with the same or syndromic tumor

≥2 first-degree relatives with rare tumors

≥3 close relatives with the same or related/syndromic tumors

Genetic testing is often more informative if it can be started with a family member with a previous or current cancer diagnosis than with someone who has never had cancer.

Suppose a family member has already been diagnosed with a hereditary cancer syndrome. In this case, all family members who may have inherited genetic variants should consider genetic testing, even if they have not (yet) had cancer.

Knowing about the risks allows patients to increase awareness and, if necessary, seek advice from specialists in relevant specialties (e.g., general physicians, oncologists, reproductive specialists), timely cancer screening and diagnostics, and determine the treatment tactics, management, and preventive measures.

Reference

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/hereditary-cancer syndrome
Hereditary syndromes associated with neuroendocrine tumors, Oleinikov, K., Grozinsky-Glasberg, S., Current Opinion in Endocrine and Metabolic Research, Vol 18, 2021, p. 230–235, doi.org/10.1016/j.coemr.2021.03.018.
https://www.cancer.org/cancer/ovarian-cancer/causes-risks-prevention/risk-factors.html
Diagnosis and management of hereditary cancer: tabular based clinical and genetic aspects, Henson, J. W., Resta, R. G. Elsevier, 2021, ISBN978—0—323—90746—0, https://doi.org/10.1016/C2020—0—02965—8
Handbook of clinical cancer genetics, Matloff, E. T., published by LWW, 2013, ISBN13: 978—1—4511—9098—4.