“Cancer on their genome. These mutations called “passenger mutations”.

“Cancer as a genetic disease: What is the molecular basis of inherited breast cancer”

Cancer is one of the most common and fatal disease worldwide, projected with more than 1.6 million new cases and 600 thousand deaths in the United States in 20171. In females, most prevalent malignancies are breast, lung and colon cancer, respectively. Prostate, lung and colon cancers are the most prevalent cancer, respectively, in males. Cancer is not a single clinical situation, but rather consist of different forms and stages affecting almost all type of tissue in body. Six distinguishing features of cells help the generating tumors in a multistep way. These including continuous activating proliferative signaling pathways, escaping tumor suppressors, evading programmed cell death, acquire infinite replication potential, increasing angiogenesis, and ability to invade distant tissues of the organism2. These hallmarks are very important to understand fundamental molecular basis of cancer.

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Cancer is a genetic disease even if it presents in somatic tissues or inherited from generations to generations in family. Majority of cancer caused by activating gain of function mutations of oncogenes and inactivating loss of function mutations of tumor suppressor genes. These mutations called “driver mutations” that drive the promoting cancer. After normal cells become tumor cells they continue to develop new mutations on their genome. These mutations called “passenger mutations”. Different type of changes in genetic architecture resulted in tumor formation such as chromosomal alterations (translocations, inversions, duplications, deletions), point mutations of coding and noncoding genes and epigenetic modifications. Tumor cells proliferating faster than normal cells, thereby it develops more mutations and caused genomic instability. Genomic instability is a major feature of almost all malignancies. Telomere sequences is also important for tumor development because cancer cells are immortal. They escape from senescence because of most of the tumor cells has a telomerase activity.

Breast cancer is a highly heterogeneous and complex disease, consist of multiple subtypes and each type has distinct biological properties3. In 1866 Pierre P. Broca first described an extended family pedigree which their individuals suffer from breast cancer. He observed primary and secondary forms of tumors but not use metastasis term and also he recognized that breast cancer is an inherited disease but latent in early life then become apparent in later of life4. Breast cancer is the most prevalent type of malignancy among women and more than 10% lifetime risk seen in general female population. Majority of breast cancer cases are not inherited and called sporadic. However, approximately 20-25% of breast cancer cases carry dominantly inherited mutations which effecting susceptibility to breast cancer5.

Inherited breast cancer families have some unique features compared to sporadic cases: more than one individual has breast cancer, multiple type of cancer seen in same individual, age at onset is early, usually occur bilateral and frequently seen breast cancer in male. Researchers found that at least 10 genes associated this type of predisposition to the breast cancer6. Breast cancer 1 gene (BRCA1) and Breast cancer 2 gene (BRCA2) mutations are the most frequent cause of hereditary breast cancers. The prevalence of germline mutations of both two genes nearly 1 in 400 to 1 in 8007. Together these two genes responsible for approximately one third of highly penetrant autosomal dominant inherited breast cancer. The lifetime risk for BRCA1/2 mutation carrier estimated between 40-80% in female heterozygotes. Moreover, mutations in BRCA2 also responsible for 10% to 20% of male breast cancer8. BRCA1 and BRCA2 genes encode ubiquitously expressed nuclear proteins that are known as a tumor suppressors which support genome integrity by organizing the cell cycle checkpoint control, DNA repair pathways and prevent developing any kind of cancer in normal situations. They detect and repair DNA damage such as double-strand breaks with many other tumor-suppressor proteins. More than thousand different loss of function mutations occur in these genes. Mutations of BRCA1/2 genes also related with significant increase in the risk of ovarian, prostate, pancreatic cancer. Another important issue that BRCA1 and BRCA2 genes ubiquitously expressed in all tissues but BRCA1/2 associated cancers mostly occurs breasts and ovaries. A recent study revealed that there is a connection between phosphatidylinositol 3-kinase (PI3K) and NRF2 pathways and this feature is fundamental for tissue-specific breast cancer9.  

Both BRCA1 and BRCA2 genes mostly carry loss of function mutations, but how these type mutations cause the breast cancer? To understand this question, we must learn two fundamental features of cancer. First is Knudson’s two-hit hypothesis. In 1971 Alfred G. Knudson published his clinical observations on Retinoblastoma patients and developed a statistical hypothesis10. In this hypothesis Knudson propose that hereditary form of cancer caused when the patient carry two mutations and one of them present in germ cells and inherited from parents and other mutation occur somatic cells. Dominant form of hereditary cancer well known before two-hit hypothesis which is caused by mutations of oncogenes, but after that time recessive mode of inheritance of cancer is developed. This led to researchers to find second fundamental feature of hereditary cancer which is Loss of Heterozygosity. Tumor suppressor genes also found after this hypothesis, firstly RB1 gene cloned in 1986 and then BRCA1 gene mapped to the chromosome 17q21 in 199011. After mapping of early onset familial breast cancer gene, many labs work four years to positional mapping and BRCA1 gene sequence published in 199412. A further investigation of BRCA1-negative cases led to the determination of BRCA2 gene on chromosome 13q1213.

Deleterious mutations of other genes which are critical for DNA repair and genomic integrity that create predisposition to familial breast cancer including TP53, PALB2, CHEK2, BARD1, BRIP1, ATM, RAD51C, and RAD51D14. With the advent of next generation sequencing technology new information continually come from large studies to understand familial breast tumors. An extensive work shed light to molecular basis of human breast cancer15. However, the great number of genetic factors to inherited breast cancer remain unknown.

There are two certain characteristics of all breast cancer predisposing genes. One of them is that single destructive mutation is sufficient to increase breast cancer risk. And second is that genes have many deleterious mutations but individually rare. Inherited breast cancer has extreme allelic and locus heterogeneity and it can be use a model for other complex diseases which “common disease-multiple rare allele” description best fit for this type of diseases6.

Early detection of women at risk for development of breast and ovarian cancer possible with using DNA sequencing of these predisposing genes. Determining of clearly disease-causing mutations is very important and helpful for genetic counseling, prediction of lifetime risk for development of breast cancer in cases, precision medicine and personalized genomics. There are many gene panels available to detection of deleterious mutations in all the genes associated with familial breast cancer, even genome-wide sequencing to determine other candidate genes is possible14. It would be possible to screening all population in a country rather than individuals who has familial history of breast cancer in future.

 

References

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3      B. Weigelt and J. S. Reis-Filho, “Histological and molecular types of breast cancer: Is there a unifying taxonomy?,” Nature Reviews Clinical Oncology, vol. 6, no. 12. pp. 718–730, 2009.

4      P. P. Broca, Traite des Tumeurs. Paris, 1866.

5      H. T. Lynch, C. Snyder, and M. J. Casey, “Hereditary ovarian and breast cancer: What have we learned,” Ann. Oncol., vol. 24, no. SUPPL.B, 2013.

6      T. Walsh and M.-C. King, “Ten Genes for Inherited Breast Cancer,” Cancer Cell, vol. 11, no. 2, pp. 103–105, Feb. 2007.

7      N. Petrucelli, M. B. Daly, and G. L. Feldman, “Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2,” Genet. Med., vol. 12, no. 5, pp. 245–259, 2010.

8      F. W. Nussbaum, Robert L; McInnes, Roderick R; Huntington, Thompson & Thompson Genetics in Medicine. 2016.

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10    A. G. Knudson, “Mutation and Cancer: Statistical Study of Retinoblastoma,” Proc. Natl. Acad. Sci., vol. 68, no. 4, pp. 820–823, 1971.

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12    M. C. King, “‘The race’ to clone BRCA1,” Science (80-. )., vol. 343, no. 6178, pp. 1462–1465, 2014.

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14    F. J. Couch, K. L. Nathanson, and K. Offit, “Two decades after BRCA: Setting paradigms in personalized cancer care and prevention,” Science (80-. )., vol. 343, no. 6178, pp. 1466–1470, 2014.

15    T. C. G. A. Network, “Comprehensive molecular portraits of human breast tumours,” Nature, vol. 490, no. 7418, pp. 61–70, 2012.