Читать книгу Constitutional Oncogenetics - Noureddine Boukhatem - Страница 12

This book offers a concise and precise state of the art in the field of genetic predisposition to cancer. It provides an up-to-date overview of a field that is still in the process of maturing. The emphasis is on clinical aspects in relation to the practice of oncogenetic counseling as undertaken in France based on my experience in three oncogenetic services (the Centre Jean-Perrin in Clermont-Ferrand, the Institut Gustave-Roussy and the Institut Curie in Paris).

In Parts 1 and 2, which are the focus of this book, we catalogue the genetic predisposition syndromes for cancer. We deal with the syndromes in order of frequency, as deduced from statistics on patients and their relatives carrying a genetic alteration predisposing to cancer and identified in 2016 by the various accredited centers reported by the Institut National du Cancer.

Thus, in Part 1, we start with breast/ovarian cancer predisposition syndrome and Lynch syndrome, of which the suspicion of their presence is the primary reason for oncogenetic consultations. Genetic alterations predisposing to these two syndromes identified in index patients and their relatives in 2016 in France represented 67% of all genetic predispositions to cancer (breast/ovary 53% and Lynch 14%). We then deal with the other syndromes for which the percentage of genetic alterations identified as predisposing them is greater than 1%. In Part 2, we describe the syndromes for which the percentage of genetic alterations predisposing them is less than 1%.

DEFINITION.– The term index case (patient zero) is used to refer to the first person in an outbreak to have been infected with a pathogen. Here, the index case or index patient is the first person in a family where a genetic abnormality (mutation in the broadest sense) has been detected.

DEFINITION.– The term relative refers to a person who has a family (blood) relation to the index case.

DEFINITION.– The term syndrome refers to a group of several symptoms characteristic of a specific disease, constituting a recognizable clinical entity and attributable to a certain cause.

DEFINITION.– The term genetic predisposition refers to an increased likelihood or probability of developing a particular disease due to the presence of one or more mutations in the gene and/or a family history indicating an increased risk of the disease. It is also known as genetic susceptibility.

In this book, we consider the syndromes of genetic predisposition to cancers that were diagnosed in France in 2016 (see Table I.1). These syndromes are classified here (see Table I.2) according to statistics on index patients and their relatives carrying a genetic alteration predisposing to cancer, identified in the various accredited centers in France in 2016.

The national organization of oncogenetics in France, under the aegis of the INCa, is a unique and efficient model enabling complete care of the families concerned. Figure I.1, reproduced from the INCa report cited above, gives a summary of the path of index patients and their relatives through the oncogenetic circuit.

Table I.1 Statistics on index patients and their relatives carrying a genetic alteration predisposing to cancer, identified in in 2016 by the various accredited centers in France

Predispositions	Genes	AR	IC+	REL+	Total
Breast ovarian syndrome (including isolated ovarian cancers)	BRCA1	/	893	1,280	4,356
BRCA2	/	777	1,165
PALB2	/	64	51
RAD51	/	16	8
Other	/	12	0
Lynch syndrome	MLH1	/	128	203	1,148
MSH2	/	163	236
MSH6	/	116	134
PMS2	/	54	93
EPCAM	/	6	10
Other*	/	1	4
APC	/	128	148
Familial adenomatous polyposis	MUTYH	BI	64	20	528
MONO	72	86
POLE	/	4	4
POLD1	/	1	0
NTHL1	BI	1	0
MONO	0	0
Hereditary diffuse gastric cancer	CDH1	/	11	36	47
Endocrine neoplasia	MEN1	/	45	61	213
RET	/	40	64
CDKN1B	/	3	0
Von Hippel–Lindau syndrome	VHL	/	28	17	45
Hereditary paraganglioma– pheochromocytoma	SDH	/	66	98	184
MAX	/	5	5
TMEM127	/	2	6
EPAS1	/	2	0
Familial pituitary adenomas	AIP	/	10	4	14
Ataxia–telangiectasia	ATM	BI	23	5	59
MONO	2	27
MRE11A	BI	0	0
MONO	0	2
Hereditary papillary renal carcinoma	FH	/	20	12	37
MET	/	3	2
Hematologic malignancies	**	/	14	1	15
Hyperparathyroidism	CDC73	/	19	16	51
CASR	/	16	0
Cowden syndrome	PTEN	/	24	21	51
PIK3CA	/	6	0
Fanconi syndrome	FANC	BI	17	10	50
MONO	5	17
RAD51	BI	0	0
MONO	0	1
Familial malignant melanoma	CDKN2A	/	28	26	120
BAP1	/	31	11
MITF	/	20	0
POT1	/	3	0
CDK4	/	1	0
Neurofibromatosis	NF1	/	430	137	682
NF2	/	36	3
LZTR1	/	30	3
SMARCB1	/	10	3
SPRED1	/	18	8
SMARCE1	/	4	0
RASopathies and Noonan syndrome	***	/	159	NR	159
Retinoblastoma	RB1	/	29	6	35
Birt–Hogg–Dubé syndrome	FLCN	/	112	55	167
Bloom syndrome	BLM	BI	0	2	5
MONO	0	3
Carney complex	ARMC5	/	10	5	18
PRKAR1A	/	1	2
Gorlin syndrome	PTCH1	/	101	17	120
PTCH2	/	1	0
SUFU	/	1	0
Li–Fraumeni syndrome	TP53	/	31	39	71
CHEK2	/	1	0
Peutz–Jeghers syndrome	STK11	/	12	9	21
Juvenile polyposis syndrome	BMPR1A	/	7	9	36
SMAD4	/	11	9
Werner syndrome	WRN	BI	1	0	3
MONO	0	2
Xeroderma pigmentosum	XP	BI	11	15	43
MONO	3	14

COMMENT ON TABLE I.1.– Genes: names of the genes directly linked to the predisposition mentioned and which were reported in a diagnostic report, in France, in 2016. IC+: Index cases identified in 2016 as carriers of a genetic alteration in the genes mentioned; REL+: relatives identified in 2016 as carriers of a genetic alteration in the genes mentioned; AR: allelic status for genes with autosomal recessive transmission; BI: index or relatives carrying biallelic mutations; MONO: index or relatives carrying a monoallelic mutation; *constitutional hypermethylation of the promoter of the MLH1 gene; **CEBPA, ETV6, GATA2, KIT, MPL, SBDS, SH2B3, SRP72, WAS, etc.; ***BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, SOS2, etc.

DEFINITION.– DNA methylation is the enzymatically controlled addition of a methyl group to a nucleotide base (such as cytosine in eukaryotes) in a DNA molecule that plays a role in the regulation of gene expression (e.g., by inhibiting gene transcription).

Table I.2 Order of syndromes according to their frequency (as deduced from statistics on index patients and their relatives carrying a genetic alteration predisposing to cancer, identified in the various accredited centers in France in 2016). *IC+ and REL+: index patient and relatives

Genetic predisposition to cancer	*IC+ and REL+	%	Rank
Breast ovarian syndrome (including isolated ovarian cancers)	4,356	52.62	1
Lynch syndrome	1,148	13.87	2
Neurofibromatosis	682	8.24	3
Familial adenomatous polyposis	528	6.38	4
Endocrine neoplasia	213	2.57	5
Hereditary paraganglioma–pheochromocytoma	184	2.22	6
Birt–Hogg–Dubé syndrome	167	2.02	7
RASopathies and Noonan syndrome	159	1.92	8
Familial malignant melanoma	120	1.45	9
Gorlin syndrome	120	1.45	10
Li–Fraumeni syndrome	71	0.86	11
Ataxia–telangiectasia	59	0.71	12
Hyperparathyroidism	51	0.62	13
Cowden syndrome	51	0.62	14
Fanconi syndrome	50	0.60	15
Hereditary diffuse gastric cancer	47	0.57	16
von Hippel–Lindau syndrome	45	0.54	17
Xeroderma pigmentosum	43	0.52	18
Hereditary papillary renal carcinoma	37	0.45	19
Juvenile polyposis syndrome	36	0.43	20
Retinoblastoma	35	0.42	21
Peutz–Jeghers syndrome	21	0.25	22
Carney complex	18	0.22	23
Hematologic malignancies	15	0.18	24
Familial pituitary adenomas	14	0.17	25
Bloom syndrome	5	0.06	26
Werner syndrome	3	0.04	27
Total	8,278	100	/

DEFINITION.– Hematologic malignancies are hematologic cancers: cancers that occur in hematopoietic tissues, such as bone marrow, or in cells of the immune system. Leukemia, lymphoma, and multiple myeloma are examples of hematological cancers, also called blood cancer.

Figure I.1. Global path of the index patient and their family members in the oncogenetic circuit in France