Family, a source of happiness, a fortune of joy.. Sharing happiness and troubles with equal grace and smile, A bond of
memories and love inherited with generations and beyond,But there is something more which unknowingly comes
along... Making us doubt whether a silent threat of cancer is being woven across...?
All cancer is genetic but most are not inherited! It's often heard. Small yet significant, these inherited cancers accounts
for around 5% of all cancers. Basically the term cancer is used to define diseases which involves abnormal growth and
uncontrolled cell division that can invade nearby tissues. There are two types of abnormal tumorous growth, namely
Benign (confined to its original location) and Malignant (that spreads to other parts of body).
Modes of Origin
- Sporadic
or non-hereditary Sporadic cancers, as the name implies are those cancers which arise randomly due to gene damage
acquired from environmental exposures, dietary aspects, hormones, normal aging, and other factors. Most of these genetic
changes are neither shared with relatives nor passed on to subsequent generations.
- Hereditary
Hereditary cancers are those form of cancers which are passed on from one generation to other and often occur earlier
than the sporadic form of the same cancer. Hence, different types of screening are often recommended for people at
younger age carrying gene mutation or have a family history of hereditary cancers.
- Familial cancer
Familial cancer, is named so as it occurs more often in families, than would be expected by chance; along with significant
involvement of environmental or lifestyle factors such as smoking or other carcinogenic factors. These cancers have shown
to affect most major organ systems including colon, breast, ovary and skin.
Salient Features of Family Cancer Syndrome (FCS)
- Many cases of the same type of cancer, especially the rare or uncommon ones such as breast cancer in a man,
in the family
- Occurrence at relatively young age and earlier than usual
- more than one type of cancer observed in a single person
- Cancer is usually found in both pair of organs such as both eyes, kidneys or breasts
- More than one childhood cancer in siblings
- Failure of the disease to appear in unrelated lines such as in spouses or in-laws.
Inheritance Pattern in FCS
- Autosomal Dominant
In this case, there is a 50% chance of transfer of the genetic mutation from parent to each offspring, e.g. Neurofibromatosis.
- Autosomal Recessive
Usually both parents stay unaffected as they acts as a carrier, and increases the risk of transmission to offspring by 25%, e.g.
Dyskeratosis congenita.
- Genomic Imprinting
Epigenetic inclusion with the transfer being specific; dependent on parent of origin, e.g. Familial para gangliomas.
Commonly Witnessed Types of Familial Cancers
Multiple Endocrine Neoplasia (MEN)
MEN, an autosomal dominant disorder is marked by the occurrence of tumors that are derived from neural crest and
involves two or more endocrine glands. Four major types of MEN usually recognized are- MEN type 1-4, wherein,
each form is characterized by the development of tumors within specific endocrine glands.
- MEN1 types are due to mutations in the nuclear protein encoding the gene-menin.
- MEN2 (previously known as MEN2a) occurs because of mutations of a tyrosine kinase receptor encoded by the
rearranged during transfection (RET) protoncogene.
- MEN3 was previously known as MEN2b and are caused due to RET mutations.
- MEN4 also known as Syndrome X is seen in individuals having cyclin-dependent kinase inhibitor (CDNK1B) mutations.
Familial Retinoblastoma
It is one of the most found childhood intraocular tumor with 90% of its cases being diagnosed before the age of 5 years
globally. Its affects approximately 1 in 15,000 to 20,000 live births worldwide.' Due to better treatment modalities and
early diagnosis, its prognosis has significantly improved over the years. Delaying its diagnosis is believed to be the most
crucial factor for poor prognosis in managing retinoblastoma (Rb). It is mainly seen in developing countries leading to its
advancement with less survival rates.
It develops due to the mutation in RB1 gene and 60% of the affected individuals have unilateral Rb and rest 40% have
bilateral Rb. Strabismus (cross-eyed or wall-eyed vision) and Leukocoria (reflection from retina of the eye) are the most
frequently observed clinical manifestations.
Lynch Syndrome
Lynch syndrome or Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is an inherited disorder which mostly increases
the risk for cancers of colon and rectum. It can also cause cancers of stomach, liver, gallbladder, small and large intestine,
brain, upper urinary tract and skin.
Mutation in one of the four genes of DNA mismatch repair system leads to HNPCC. The prevalence is around 1 in 500 in
the general population and is responsible for 2% to 3% of all colorectal cases. Development of colorectal cancer at around
45 years of age, located in the proximal colon in two-thirds of cases; along with the occurrence of extracolonic tumors such
as in ovaries, stomach or others are the basis by which it is characterized.
Hereditary Breast and Ovarian Cancer (HBOC)
It is a le It is a leading type of cancer affecting women across the world and is mainly due to mutations in BRCA1/2 genes.
Mutations in other genes have a minor role because of its low prevalence or penetrance. It occurs in 5-10% of all the hereditary
cancer cases. BRCA mutation carriers have 60% risk of developing breast cancer and ovarian cancer with risk of up to 55%
for an age-dependent contralateral breast cancer.
HBOC is characterized by increased risk for female as well as male breast cancer and ovarian cancer. However, the risk is
relatively lower for melanoma and other cancers like prostate or pancreatic in individuals with a BRCA2 pathogenic variant.
Epidemiological evidence has consistently pointed to family history as a strong and independent predictor of breast cancer
risk. Thus, women with a first-degree relative (mother or sister) who has been diagnosed with breast cancer are at elevated
risk for development of the disease in them.
Li-Fraumeni Syndrome
This syndrome was first reported by Li and Fraumeni in 1969. A classical cancer predisposition disorder which is characterized
by appearance of tumors in multiple organs mostly at an early age. It is a hereditary condition which is commonly associated
with germinal mutation in the TP53 gene, which codes for p53 tumor suppressor gene. A study carried out to determine the
cancer risk for gene mutation in carriers and non carriers; showed that 12%, 35%, 52% and 80% of the carriers developed cancer
by ages of 20, 30, 40 and 50 years, respectively. Breast cancer, adrenocortical carcinoma and soft tissue sarcomas were the
most common cancers. While, the non carriers had 0.7%, 1.0%, 2.2% and 5.1% of risk for the same ages, respectively. The same
study also showed that risk for cancer was higher in female carriers than males.
Von Hippel Lindau Syndrome
It is named after a German ophthalmologist Eugen von Hippel and a Swedish pathalogist, A. Lindau. Von Hippel-Lindau (VHL)
syndrome is a multi-organ, familial neoplastic syndrome, and results due to genetic aberrations of the tumor suppressor gene
VHL. The disease affects 1 in 36,000 live births and its inheritance pattern occurs in an autosomal dominant fashion, with a
penetrance of over 90%.
Common VHL-associated tumors include hemangioblastomas (brain, spinal cord, and retina), renal cell carcinoma and
pancreatic neuroendocrine tumors. Affected individuals are predisposed to germline mutations of the VHL gene resulting
in benign and malignant tumors in central nervous system and visceral organs such as kidneys, pancreas, adrenals and
reproductive organs.
Catalyst to Awareness
Angelina Jolie's mastectomy in May 2013 gathered a huge public attention towards the prophylactic mastectomy. The
famous Hollywood actress underwent prophylactic mastectomy due to the BRCA gene mutations. Many studies described
it as "Angelina Jolie Effect" and concluded that it caused a major impact on genetic enquiries.
This announcement may have lessen the fears of cancer from the patients and encouraged them to consider genetic testing
as a screening tool and thereby reduce the cancer risks. However, lack of awareness, stigma of carrying genetic mutation and
economic conditions still remain the biggest barriers for individuals in developing countries. Therefore, education of the
general public is extremely essential to make people aware, broaden their knowledge and opinion about familial cancer.
